Organic compounds

ABSTRACT

The invention relates to organic compounds which have interesting pharmaceutical properties. In particular, the compounds are useful in the treatment and/or prevention of infections such as those caused by  Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Trypanosoma cruzi  and parasites of the  Leishmania  genus such as, for example,  Leishmania donovani . The invention also relates to pharmaceutical compositions containing the compounds, as well as processes for their preparation.

TECHNICAL FIELD

This invention is directed to, inter alia, novel compounds which areuseful as pharmaceuticals. The invention is also directed topharmaceutical compositions containing the compounds, processes fortheir preparation and uses of the compounds in various medicinalapplications, such as for the treatment of parasitic diseases, e.g.malaria, leishmaniasis and Chagas disease. Compounds are also providedwhich are useful as intermediate for example the Boc compounds)

BACKGROUND

Malaria is an old infectious disease caused by four protozoan parasites,Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae andPlasmodium ovale. These four parasites are typically transmitted by thebite of an infected female Anopheles mosquito. Malaria is a problem inmany parts of the world, and over the last few decades the malariaburden has steadily increased. An estimated 1 to 3 million people dieevery year from malaria—mostly children under the age of 5. Thisincrease in malaria mortality is due in part to the fact that Plasmodiumfalciparum, the deadliest malaria parasite, has acquired resistanceagainst nearly all available antimalarial drugs, with the exception ofthe artemisinin derivatives.

Leishmaniasis is caused by one of more than twenty (20) varieties ofparasitic protozoa that belong to the genus Leishmania, and istransmitted by the bite of female sandflies. Leishmaniasis is endemic insome 90 countries, including many tropical and sub-tropical areas.

There are four main forms of leishmaniasis. Visceral leishmaniasis, alsocalled kala-azar, is the most serious form and is caused by the parasiteLeishmania donovani. Patients who develop visceral leishmaniasis can diewithin months unless they receive treatment. The two main therapies forvisceral leishmaniasis are the antimony derivatives sodiumstibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®).Sodium stibogluconate has been used for about 70 years and resistance tothis drug is a growing problem. In addition, the treatment is relativelylong and painful, and can cause undesirable side effects.

Human African Trypanosomiasis, also known as sleeping sickness, is avector-borne parasitic disease. The parasites concerned are protozoabelonging to the Trypanosoma Genus. They are transmitted to humans bytsetse fly (Glossina Genus) bites which have acquired their infectionfrom human beings or from animals harbouring the human pathogenicparasites.

Chagas disease (also called American trypanosomiasis) is another humanparasitic disease that is endemic amongst poor populations on theAmerican continent. The disease is caused by the protozoan parasiteTrypanosoma cruzi, which is transmitted to humans by blood-suckinginsects. The human disease occurs in two stages: the acute stage, whichoccurs shortly after the infection, and the chronic stage, which candevelop over many years. Chronic infections result in variousneurological disorders, including dementia, damage to the heart muscleand sometimes dilation of the digestive tract, as well as weight loss.Untreated, the chronic disease is often fatal.

The drugs currently available for treating Chagas disease are nifurtimoxand benznidazole. However, problems with these current therapies includetheir adverse side effects, the length of treatment, and the requirementfor medical supervision during treatment. Furthermore, treatment isreally only effective when given during the acute stage of the disease.Resistance to the two frontline drugs has already arisen. The antifungalagent amphotericin b has been proposed as a second-line drug, but thisdrug is costly and relatively toxic.

In view of the foregoing, it is desirable to develop novel compounds forevaluation and use as antiparasitic agents.

SUMMARY OF INVENTION

In a first aspect, the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, ester or prodrug thereof

-   -   wherein    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy, amine or aryl        optionally substituted with one or more substituents    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   either (i) R3 is H or alkyl;    -   R4 is H, alkyl, hydroxyalkyl, —COOD wherein D is an alkyl group        or    -   (ii) R3 and R4 form part of a heterocyclo ring; R5 is H or        alkyl;    -   n is 1, 2 or 3; and    -   A and B are fused to, and form part of, an unsubstituted or        substituted monocyclic or polycyclic arene or heteroarene;    -   provided that if A and B are fused to and take the part of        positions 2 and 3 of an unsubstituted indole, n is 1 or 2, R2        and R3 are H, m is 1 and R1 is in position 6 of the spiro        oxindole, then        -   (i) R1, R4 and R5 are not all H; or (ii) if R1 is H,            then (a) R4 is not methyl when R5 is H and (b) R5 is not            methyl when R4 is H; or        -   (iii) if R1 is Br, then (a) R4 and R5 are not both H,            and (b) R4 is not methyl when R5 is H, and (c) R5 is not            methyl when R4 is H.

Haloalkyl is preferably trifluoromethyl. Amino may be e.g. substitutedby one or two substituents e.g. lower alkyl.

In the above formula, R1 may be, for example, F, Cl, Br, methyl, —CF₃,—OCH₃, —N(CH₃)₂, —C₆H₅, —(C₆H₄)CF₃ or —(C₆H₄)O(C₆H₅). In some examples,R1 may be di-Cl when m is 2. In other examples R1 may be Cl when m is 1.Conveniently the R1 may be para or ortho to the nitrogen atom (position5 or 6 of the spiro).

R2 may be e.g. methyl, Bn or Boc (for the meanings of abbreviationsplease see later).

R3 may be methyl. R4 may be methyl, ethyl, propyl, isopropyl, —CH₂OH,—COOCH₃ or —COOCH₂CH₃. In some examples, R3 and R4 may together form adi-valent substituent of formula (i):

In some examples, R4 and R5 may both be methyl.

A and B may be fused to and form part of imidazole, benzene or indole.In some examples, A and B may be fused to and form part of benzenesubstituted with an electron donating group (EDG) in one of the 4remaining positions. In other examples, A and B may be fused to and formpart of a substituted indole of formula (a):

-   -   p may be 1, 2, 3 or 4 and R6 may be one or more of a group        comprising halogen, haloalkyl, alkoxy, hydrogen, hydroxyl, and        nitrile. or (b):

-   -   wherein R7 may be alkyl, alkoxycarbonyl, aryl carbonyl or aryl        sulfonyl. A and B form part of the 2 and 3 positions of the        indole.

In some examples, R6 may be C₁, CF₃ or —OCH₃.

In some examples, R7 may be methyl, Boc or a substituent of formula(ii), (iii), (iv) or (v):

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein    -   R1 is a halogen; and    -   R4 is alkyl, hydroxyalkyl or —COOD wherein D is an alkyl group;    -   provided that if R1 is Br, R4 is not methyl.

In the above formula, R1 may be Br or Cl and R4 may be methyl, ethyl,propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein    -   R1 is a halogen; and    -   R4 is alkyl, hydroxyalkyl or —COOD wherein D is an alkyl group;    -   provided that if R1 is Br, R4 is not methyl.

In the above formula, R1 may be Br or C1 and R4 may be methyl, ethyl,propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein R7 is aryl carbonyl or aryl sulfonyl.

In the above formula, R7 may be a substituent of formula (II), (iii),(iv) or (v) as defined above for the compound of formula (I).

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein R4 is alkyl.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein R4 is alkyl.

In the above formula, R4 may be methyl or ethyl.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein    -   R1 is halogen or aryl optionally substituted with one or more        substituents;    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   R4 is H or alkyl;    -   R5 is H or alkyl; and    -   R7 is H, alkyl, alkoxycarbonyl, aryl carbonyl or aryl sulfonyl,    -   provided that if R2 and R7 are H, then        -   R1, R4 and R5 are not all H; or        -   if R1 is H, then R4 is not methyl when R5 is H and R5 is not            methyl when R4 is H; or        -   if R1 is Br, then R4 and R5 are not both H, and R4 is not            methyl when R5 is H, and R5 is not methyl when R4 is H.

In the above formula, R1 may be Br, Cl, F, —C₆H₅, —(C₆H₄)CF₃ or—(C₆H₄)O(C₆H₅). R2 may be methyl, Bn or Boc. R4, R5 or both R4 and R5may be methyl. R7 may be methyl, Boc or a substituent of formula (ii),(iii), (iv) or (v) as defined above for the compound of formula (I).

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy or amine;    -   R3 is H or alkyl;    -   R4 is H or alkyl;    -   R5 is H or alkyl; and    -   R6 is H, halogen, haloalkyl or alkoxy;    -   provided that if R3 and R6 are H, m is 1 and R1 is in position 6        of the spiro oxindole, then        -   (i) R1, R4 and R5 are not all H; or        -   (ii) if R1 is H, then (a) R4 is not methyl when R5 is H            and (b) R5 is not methyl when R4 is H; or        -   (iii) if R1 is Br, then (a) R4 and R5 are not both H,            and (b) R4 is not methyl when R5 is H, and (c) R5 is not            methyl when R4 is H.

In the above formula, R1 may be F, Cl, Br, methyl, —CF₃, —OCH₃ or—N(CH₃)₂ and R6 may be Cl, —CF₃ or —OCH₃. In some examples, R1 may bedi-Cl when m is 2.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy, amine or aryl        optionally substituted with one or more substituents;    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   R3 is H or alkyl;    -   R4 is H, alkyl, hydroxyalkyl, —COOD wherein D is an alkyl group        or R3 and R4 form part of a heterocyclo ring;    -   R5 is H or alkyl;    -   n is 1, 2 or 3; and    -   A and B are fused to and form part of an unsubstituted or        substituted monocyclic or polycyclic arene or heteroarene;    -   provided that if A and B are fused to positions 2 and 3 of an        unsubstituted indole, n is 1 or 2, R2 and R3 are H, m is 1 and        R1 is in position 6 of the spiro oxindole, then        -   R1, R4 and R5 are not all H; or        -   if R1 is H, then R4 is not methyl when R5 is H and R5 is not            methyl when R4 is H; or        -   if R1 is Br, then R4 and R5 are not both H, and R4 is not            methyl when R5 is H, and R5 is not methyl when R4 is H.

In the above formula, R1 may be F, Cl, Br, methyl, —CF₃, —OCH₃,—N(CH₃)₂, —C₆H₅, —(C₆H₄)CF₃ or —(C₆H₄)O(C₆H₅). In some examples, R1 maybe di-Cl when m is 2. R2 may be methyl, Bn or Boc. R3 may be methyl. R4may be methyl, ethyl, propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.In some examples, R4 and R5 may both be methyl. A and B may be fused toimidazole, benzene or indole. In some examples, A and B may be fused tobenzene substituted with an electron donating group (EDG). In otherexamples, A and B may be fused to a substituted indole of formula (a) or(b) as defined above.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

-   -   wherein p may be 1, 2, 3 or 4 and R6 may be one or more of a        group comprising halogen, haloalkyl and alkoxy.

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In one embodiment, the invention relates to a compound, or apharmaceutically acceptable salt, ester or prodrug thereof, of theformula:

In another aspect, the invention provides a compound of formula (II), ora pharmaceutically acceptable salt, ester or prodrug thereof:

-   -   wherein:    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy, amine or aryl        optionally substituted with one or more substituents;    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   R3 is H or alkyl;    -   R4 is H, alkyl, hydroxyalkyl, —COOD wherein D is an alkyl group        or R3 and R4 form part of a heterocyclo ring;    -   R5 is H or alkyl;    -   n is 1, 2 or 3; and    -   A and B are fused to and form part of an unsubstituted or        substituted monocyclic or polycyclic arene or heteroarene.

In the above formula, R1 may be F, Cl, Br, methyl, —CF₃, —OCH₃,—N(CH₃)₂, —C₆H₅, —(C₆H₄)CF₃ or —(C₆H₄)O(C₆H₅). In some examples, R1 maybe di-Cl when m is 2. R2 may be methyl, Bn or Boc. R3 may be methyl. R4may be methyl, ethyl, propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.In some examples, R4 and R5 may both be methyl. A and B may be fused toimidazole, benzene or indole. In some examples, A and B may be fused tobenzene substituted with an electron donating group (EDG). In otherexamples, A and B may be fused to a substituted indole of formula (a) or(b) as defined above for the compound of formula (I).

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) or (II) or a compound of any offormulae (Ia) to (Ip) as defined above, or a pharmaceutically acceptablesalt, ester or prodrug thereof, in combination with at least onepharmaceutically acceptable excipient, e.g. appropriate diluent and/orcarrier, e.g. including fillers, binders, disintegrators, flowconditioners, lubricants, sugars or sweeteners, fragrances,preservatives, stabilizers, wetting agents and/or emulsifiers,solubilisers, salts for regulating osmotic pressure and/or buffers andoptionally a second drug substance. The pharmaceutical composition maybe used for the treatment and/or prevention of a disease caused by aparasite such as Plasmodium falciparum, Plasmodium vivax, Plasmodiummalariae, Plasmodium ovale, Trypanosoma cruzi or a parasite of theLeishmania genus such as, for example, Leishmania donovani. The diseasemay be malaria, leishmaniasis or Chagas disease.

In another aspect, the invention provides a compound of formula (I) or(II) or a compound of any of formulae (Ia) to (Ip) as defined above, ora pharmaceutically acceptable salt, ester or prodrug thereof, optionallya second drug substance, for use as a medicament.

In another aspect the invention provides the use of a compound offormula (III), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy, amine or aryl        optionally substituted with one or more substituents;    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   R3 is H or alkyl;    -   R4 is H, alkyl, hydroxyalkyl, —COOD wherein D is an alkyl group        or R3 and R4 form part of a heterocyclo ring;    -   R5 is H or alkyl;    -   n is 1, 2 or 3; and    -   A and B are fused to and form part of an unsubstituted or        substituted monocyclic or polycyclic arene or heteroarene.

In the above formula, R1 may be F, Cl, Br, methyl, —CF₃, —OCH₃,—N(CH₃)₂, —C₆H₅, —(C₆H₄)CF₃ or —(C₆H₄)O(C₆H₅). In some examples, R1 maybe di-Cl when m is 2. R2 may be methyl, Bn or Boc. R3 may be methyl. R4may be methyl, ethyl, propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.In some examples, R3 and R4 may together form a substituent of formula(I) as defined above. In some examples, R4 and R5 may both be methyl. Aand B may be fused to imidazole, benzene or indole. In some examples, Aand B may be fused to benzene substituted with an electron donatinggroup (EDG). In other examples, A and B may be fused to a substitutedindole of formula (a) or (b) as defined above for the compound offormula (I).

In one embodiment, the invention relates to the use of a compound offormula (I) or (II) or a compound of any of formulae (Ia) to (Ip) asdefined above, or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection.

In one embodiment, the invention relates to the use of a compound offormula (IIIa), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

In one embodiment, the invention relates to the use of a compound offormula (IIIa), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein    -   R1 is a halogen; and    -   R4 is alkyl, hydroxyalkyl or —COOD wherein D is an alkyl group.

In the above formula, R1 may be Br or C1 and R4 may be methyl, ethyl,propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.

In one embodiment, the invention relates to the use of a compound offormula (IIIb), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein    -   R1 is a halogen; and    -   R4 is alkyl, hydroxyalkyl or —COOD wherein D is an alkyl group.

In the above formula, R1 may be Br or C1 and R4 may be methyl, ethyl,propyl, isopropyl, —CH₂OH, —COOCH₃ or —COOCH₂CH₃.

In one embodiment, the invention relates to the use of a compound offormula (IIIc), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein    -   R1 is halogen or aryl optionally substituted with one or more        substituents;    -   R2 is H, alkyl, arylalkyl or alkoxycarbonyl;    -   R4 is H or alkyl;    -   R5 is H or alkyl; and    -   R7 is H, alkyl, alkoxycarbonyl, aryl carbonyl or aryl sulfonyl.

In the above formula, R1 may be Br, Cl, F, —C₆H₅, —(C₆H₄)CF₃ or—(C₆H₄)O(C₆H₅). R2 may be methyl, Bn or Boc. R4, R5 or both R4 and R5may be methyl. R7 may be methyl, Boc or a substituent of formula (ii),(iii), (iv) or (v) as defined above for the compound of formula (I).

In one embodiment, the invention relates to the use of a compound offormula (IIId), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein    -   m is 1 or 2;    -   R1 is H, halogen, alkyl, haloalkyl, alkoxy or amine;    -   R3 is H or alkyl;    -   R4 is H or alkyl;    -   R5 is H or alkyl; and    -   R6 is H, halogen, haloalkyl or alkoxy.

In the above formula, R1 may be F, Cl, Br, methyl, —CF₃, —OCH₃ or—N(CH₃)₂ and R6 may be Cl, —CF₃ or —OCH₃. In some examples, R1 may bedi-Cl when m is 2.

In one embodiment, the invention relates to the use of a compound offormula (IIIe), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

In one embodiment, the invention relates to the use of a compound offormula (IIIf), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

In one embodiment, the invention relates to the use of a compound offormula (IIIg), or a pharmaceutically acceptable salt, ester or prodrugthereof, for the manufacture of a medicament, e.g. a pharmaceuticalcomposition, for the treatment and/or prevention of a parasiticinfection:

-   -   wherein n is 1 or 2.

In another aspect, the invention provides a compound of formula (I),(II) or (III) or a compound of any of formulae (Ia) to (Ip) and (IIIa)to (IIIg) as defined above, or a pharmaceutically acceptable salt, esteror prodrug thereof, for use in the treatment and/or prevention of adisease caused by an infection by a parasite such as, for example,Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodiumovale, Trypanosoma cruzi or a parasite of the Leishmania genus such as,for example, Leishmania donovani.

In still another aspect, the invention provides a method of treatingand/or preventing a disease caused by a parasite such as Plasmodiumfalciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale,Trypanosoma cruzi or a parasite of the Leishmania genus such as, forexample, Leishmania donovani, comprising administering to a subject inneed thereof an effective amount of a compound of formula (I), (II) or(III) or a compound of any of formulae (Ia) to (Ip) and (IIIa) to (IIIg)as defined above, or a pharmaceutically acceptable salt, ester orprodrug thereof. The disease may be malaria, leishmaniasis or Chagasdisease.

In another aspect the invention provides a combination of a compound offormula (I), (II) or (III) or a compound of any of formulae (Ia) to (Ip)and (IIIa) to (IIIg) as defined above, or a pharmaceutically acceptablesalt, ester or prodrug thereof with at least one second drug substance.The second drug substance may be an antimalarial drug such as, forexample, artesunate, artemether, di-hydro-artemisinin, mefloquine,chloroquine, sulfadoxine, pyrimethamine, piperaquine, pyronaridine,lumefantrine or atovaquone.

In another aspect the invention provides a pharmaceutical combination,e.g. a kit, comprising a) a first agent which is a compound of formula(I), (II) or (III) or a compound of any of formulae (Ia) to (Ip) and(IIIa) to (IIIg) as defined above, in free form or in pharmaceuticallyacceptable salt form, and b) at least one co-agent. The kit may compriseinstructions for its administration.

In still another aspect, the invention provides a method for preparing acompound of formula (I), (II) or (III) or a compound of any of formulae(Ia) to (Ip) and (IIIa) to (IIIg) as defined above, comprising: reactingan amine with an isatin.

DETAILED DESCRIPTION Definitions

The term “alkyl” as used herein with reference to alkyl group refers tobranched or straight chain hydrocarbon groups, comprising preferably 1to 15 carbon atoms, preferably alkyl is lower alkyl The term “loweralkyl” as used herein refers to branched or straight chain alkyl groupscomprising 1 to 6 carbon atoms. Examples of alkyl groups include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, nonyl, decyl, etc.

The term “cycloalkyl” refers to a saturated or partially saturated(non-aromatic) ring comprising preferably 3 to 8 carbon atoms. Examplesinclude, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyland cycloheptyl.

Any alkyl group as defined above may be substituted with one or moresubstituents including, but not limited to, substituents such ashalogen, lower alkyl, lower alkoxy, hydroxy, mercapto, amino, carboxy,cycloalkyl, aryl, heteroaryl, and the like. Examples of substitutedalkyl groups include, but are not limited to, haloalkyl groups such asfluoromethyl, difluoromethyl, trifluoromethyl and pentafluoroethyl orother substituted alkyl groups such as hydroxymethyl, 1- or2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or2-carboxyethyl, and the like.

The term “aryl” as used herein refers to an aromatic ring having 6 to 18carbon atoms and includes monocyclic groups as well as multicyclic(polycyclic) groups, e.g. fused groups such as bicyclic and tricyclicgroups. Examples include, but are not limited to, phenyl group, naphthylgroup and anthracenyl group. An aryl group may be unsubstituted orsubstituted at one or more ring positions with one or more substituentsincluding, but not limited to, C₁₋₇ alkyl such as methyl, hydroxy,alkoxy, acyl, acyloxy, SCN, cyano, nitro, thioalkoxy, phenyl,heteroalkylaryl, alkylsulfonyl, halogen, acetamido, and formyl.Preferably aryl is phenyl. Preferably there are no substituents or onesubstituent.

The term “alkylaryl” as used herein refers to the group -aryl-R whereinR is an alkyl group as defined above, and aryl is as defined above. Anexample is —(C₆H₄)CF₃.

The term “arylalkyl” as used herein refers to the group -alkyl-R where Ris an aryl group as defined above, and alkyl is as defined above. Anexample is benzyl.

The term “heterocyclo” or “heterocyclic” means a saturated or partiallysaturated (non-aromatic) ring having 5 to 18 atoms, including at leastone heteroatom, such as, but not limited to, N, O and S, within thering. The heterocyclic group may be unsubstituted or substituted withone or more substituents, including but not limited to, alkyl, halogen,alkoxy, hydroxyl, mercapto, carboxy, and phenyl. The heteroatom(s) aswell as the carbon atoms of the group may be substituted. Theheterocycle may optionally be fused or bridged with one or more benzenerings and/or to a further heterocyclic ring and/or to an alicyclic ring.

The term “heteroaryl” means an aromatic ring having 5 to 18 atoms,preferably 5 or 6 atoms, including at least one heteroatom, such as, butnot limited to, N, O and S, within the ring. The term “heteroaryl”includes monocyclic groups as well as multicyclic groups, e.g. fusedgroups such as bicyclic and tricyclic groups. The heteroaryl group maybe unsubstituted or substituted at one or more ring positions with oneor more substituents including, but not limited to, alkyl, hydroxy,alkoxy, acyl, acyloxy, SCN, cyano, nitro, thioalkoxy, phenyl,heteroalkylaryl, alkylsulfonyl, halogen, and formyl. The heteroaryl mayoptionally be fused or bridged with one or more benzene rings and/or toa further heteroaryl ring and/or to an alicyclic ring.

Examples of heterocyclic and heteroaryl groups include, but are notlimited to, morpholinyl, piperazinyl, piperidinyl, pyridyl,pyrrolidinyl, pyrazinyl, pyrimidinyl, purinyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, carbazolyl, carbolinyl,cinnolinyl, indolyl, isoindolyl indolinyl, imidazolyl, indolazinyl,indazolyl, morpholinyl, quinoxalinyl, quinolyl, isoquinolyl,quinazolinyl, 1,2,3,4-tetrahydroquinolinyl, tetrahydropyranyl,tetrazolopyridyl, thiadiazolyl, thienyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, pyridyl (e.g. pyridine-2-only), thiomorpholinyl,dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, didhydrofuranyl, dihydroimidazolyl,dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazoll, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl,dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl,tetrahydrofuranyl, tetrahydrothienyl, thiazolyl, isothiazolyl,isoxazolyl, imidazolyl, indanyl, naphthpyridinyl, oxadiazolyl, oxazolyl,oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyridopyridinyl,pyridazinyl, pyrrolyl, pyrazolyl, pyrrolyl, phenanthridinyl, triazolyl,thienyl, furanyl, isobenzofuranyl, or tetrazolyl, particularlyN-containing heterocycles such as pyridyl, piperidinyl, pyrimidinyl,pyrrolidinyl, piperazinyl, quinazolinyl, 2,2,6,6-tetramethylpiperidyland morpholinyl.

The term “arene” as used herein refers to a monocyclic or polycyclicaromatic hydrocarbon compound. Examples of arenes include, but are notlimited to, benzene, naphthalene, toluene, xylene, styrene,ethylbenzene, cumene, and generally benzene rings with one or morealiphatic side chains or substituents.

The term “heteroarene” as used herein refers to a heterocyclic compoundformally derived from an arene by replacement of one or more methine(—C═) and/or vinylene (—CH═CH—) groups by trivalent or divalentheteroatoms, respectively, in such a way as to maintain the continuousπ-electron system characteristic of aromatic systems and a number ofout-of-plane π-electrons corresponding to the H{acute over (ν)}ckel rule(4n+2) (wherein n is an integer). Examples of heteroarenes include, butare not limited to, thiophene, furan pyridine and preferably indole

The term “alkoxy” as used herein refers to the group —OR wherein R isalkyl as defined above. The term “lower alkoxy” has a correspondingmeaning to the term “lower alkyl” as defined above. Examples of loweralkoxy groups include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

The term “carbonyl” as used herein refers to the group —C(═O)—.

The term “alkoxycarbonyl” as used herein refers to the group —CORwherein R is an alkoxy group as defined above. An example is Boc.

The term “arylcarbonyl” as used herein refers to the group —COR whereinR is an aryl group as defined above.

The term “sulfonyl” as used herein refers to the group —SO₂—.

The term “arylsulfonyl” as used herein refers to the group —SO₂R whereinR is an aryl group as defined above.

The term “hydroxyalkyl” as used herein refers to the group —ROH whereinR is an alkyl group as defined above.

The term “ether” as used herein refers to a group represented by theformula —ROR′, wherein R and R′ can be, independently, an alkyl, aryl,heteroaryl, cycloalkyl or heterocycloalkyl group as defined above.

The term “amino” as used herein refers to a group of formula —NRR1′wherein each of R and R1 is independently an alkyl group as definedabove of hydrogen.

The term “halo” or “halogen” as used herein refers to F, Cl, Br or I.

The term “ester” as used herein refers to the group —COOR wherein R isan alkyl or aryl group as defined above.

The term “spiro” as used herein refers to a cyclo group attached toanother ring via one carbon atom common to both rings.

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen atom on one or more atoms, e.g. C, Oor N, of a molecule; conveniently one or two atoms are replaced.

Any hydrocarbon chain which is not otherwise discussed hereinconveniently contains one or two carbon atoms when non-cyclic and 6carbon atoms when cyclic The term “alkylene” is typically of 2 carbonatoms.

The term “prodrug” as used herein means a pharmacologically acceptablederivative of the compound of formula (I), (II), (III) or (IV) asdefined above, such that an in vivo biotransformation of the derivativegives the compound as defined in formula (I), (II), (III) or (IV).Prodrugs of compounds of formula (I), (II), (III) and (IV) may beprepared by modifying functional groups present in the compounds, suchas hydroxy or acid groups, in such a way that the modified groups arecleaved in vivo to give the parent compound. Suitable prodrugs include,for example, esters or amides.

The term “salts” includes therapeutically active non-toxic acid additionsalts derived from the compounds of formula (I), (II), (III) and (IV).Acid addition salts can be obtained by treating the base form of thecompounds with appropriate acids. The compounds of the inventioncontaining acidic protons may also be converted into theirtherapeutically active non-toxic base addition salt forms by treatmentwith appropriate organic and inorganic bases. Conveniently, the acid orbase addition salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

The term “addition salt” as used in the present context also comprisesthe solvates which the compounds of the invention, as well as the saltsthereof, are able to form. Such solvates include, for example, lithium,sodium, succinate, malonate, nitrate, ammonium, phosphate, formate,carbonate, malate, hydrochloride, hydrobromide, hydroiodide, maleate,fumarate, methanesulfonate, acetate, sulfate, tartrate, citrate,para-toluenesulfonate, and trifluoroacetate.

The term “protecting group” means a group that masks a functional groupin a molecule, so that chemoselectivity is possible during a reaction.Suitable protecting groups are preferably simple to incorporate, stableto the relevant reaction conditions and easy to remove. Such protectinggroups are known to those skilled in the art and are described inProtective Groups in Organic Synthesis by Theodora W Greene (John Wiley& Sons Canada, Ltd). Suitable protecting groups include, for example,Aloc, benzoyl, benzyl, Boc, Cbz, TBS, TPDMS, Fmoc, PMB, phthalimdes,tosyl and Troc.

The term “treat”, “treating”, “treated” or “treatment” includes theprevention, diminishment or alleviation of at least one symptomassociated with or caused by the state, disease or disorder beingtreated.

The term “prevent”, “preventing” or “prevention” includes the preventionof at least one symptom associated with or caused by the state, diseaseor disorder being prevented.

The term “patient” includes organisms that are capable of sufferingfrom, or afflicted or infected with, a parasitic disease, e.g. mammalssuch as humans, cows, horses, pigs, sheep, cats, dogs, goats, mice,rabbits, rats and transgenic non-human animals. In some embodiments thepatient is a human, e.g. a human capable of suffering from, or afflictedwith, malaria.

A “parasitic disease” includes disorders and states that are associatedwith a parasitic infection in a subject.

The term “effective amount” of a compound of the invention is the amountnecessary or sufficient to treat or prevent a disease caused by aparasite such as Plasmodium falciparum, Plasmodium vivax, Plasmodiummalariae, Plasmodium ovale, Trypanosoma cruzi or a parasite of theLeishmania genus such as, for example, Leishmania donovani. Theeffective amount can vary depending on the compound employed, the modeof administration, the treatment desired and the disease indicated, aswell as other factors such as a patient's age, body weight, generalhealth and sex. One of ordinary skill in the art would be able to studythe factors described herein and make a determination regarding theeffective amount of a compound of the invention without undueexperimentation.

The term “pharmaceutical composition” includes preparations, e.g.medicaments, suitable for administration to mammals, e.g. humans.

Compounds provided by the invention are hereinafter designated as“compound(s) of the invention”. A compound of the invention includes acompound in any form, e.g. in free form, in the form of a salt, in theform of a solvate and in the form of a salt and a solvate. The compoundsof the invention embrace the compounds of formulae I, II and IIIincluding a pharmaceutically acceptable salt, ester or prodrug thereof.

It will be appreciated that any sub-genus of one substituents may becombined with another genus or sub-genus of another substituent orsubstituents.

It will be appreciated that the compounds of the invention may exist inthe form of optical isomers, racemates or diastereoisomers. The scope ofthis invention embraces all stereochemically isomeric forms of thecompounds. The term “stereochemically isomeric forms” as used hereintherefore means all possible isomeric forms which the compounds of theinvention may possess. Unless otherwise mentioned or indicated, thechemical structures, systematic names and formulae of the compoundsdenote the mixture of all possible stereochemically isomeric forms,containing all diastereomers and enantiomers of the basic molecularstructure. In particular, stereogenic centers may have the R- orS-configuration.

It will also be appreciated that the compounds of the invention canexist as tautomers, for example as keto-enol tautomeric forms. The scopeof this invention embraces all such tautomeric forms.

The compounds of the invention are useful in the treatment andprevention of infections by a pathogen, as indicated in standard invitro and in vivo tests, e.g. as described hereinafter. The pathogen maybe a parasite, in particular, a Plasmodium parasite, a Leishmaniaparasite or a Trypanosoma parasite. More particularly, the pathogen maybe Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae,Plasmodium ovale, Trypanosoma cruzi or a parasite of the Leishmaniagenus such as, for example, Leishmania donovani.

The compounds of the invention and particularly as exemplified, in freeor pharmaceutically acceptable salt form, exhibit valuablepharmacological properties, e.g. as antiparasitic agents, for example,as indicated by the tests of the Examples A and B hereinafter and aretherefore indicated for therapy.

The compounds of the invention exhibit an IC₅₀ against Plasmodiumfalciparum ranging from about 0.1 nM to about 5000 nM e.g. less thanabout 100 nM to greater than about 5000 nM, in particular less thanabout 500 nM, more particularly less than about 100 nM, still moreparticularly less than about 50 nM, and most particularly less thanabout 20 nM. Typically the compounds of the invention have activitiesmore than 5 nM. or 0.5 nM.

The required dosage for pharmaceutical use may vary inter alia dependingon the mode of administration, the particular condition to be treated,the effect desired, the compound employed, patient's age, body weight.etc In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.1 mg/kg to about 300 mg/kgper body weight, e.g. 0.01 to about 10 such as 1 to 10 mg/kg.

An indicated daily dosage in the larger mammal, e.g. humans, is in therange from about 1 mg to about 10,000 mg, e.g. 10 to 700 mg convenientlyadministered, for example, in divided doses up to six times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 10 mg to 1000 mg active ingredient. Based on the testsdescribed hereinafter, a typical daily dose for compounds in Example 50and 62 (compounds 37 and 51) for humans is about 4 mg/kg. e.g. about 300mg.

The compounds of the invention may be administered in free form or inpharmaceutically acceptable salt form

Preferred compounds are examples 50 and 62 which have theS-configuration at C3′ (the spiro indole carbon). A group of compoundscomprises those which have the same configuration at the sprio carbonatom e.g. C3′.

A further group of compounds wherein R4 is different to R5. Anadditional group of compounds have the same configuration at C1,2′ (towhich R4 and R5 are bound) as the configuration of example 48 at C1,2′

The compounds of the invention may be administered by any conventionalroute, in particular enterally, for example, orally, e.g. in the form oftablets or capsules, or parenterally, for example, in the form ofinjectable solutions or suspensions, topically, e.g. in the form oflotions, gels, ointments or creams, or in a nasal or a suppository form.

Depending on the mode of administration, the pharmaceutical compositionmay comprise from 0.05 to 99% by weight, more particularly from 0.1 to70% by weight, even more particularly from 30 to 70% by weight of theactive ingredient, and from 1 to 99.95% by weight, more particularlyfrom 30 to 99.9% by weight, even more particularly from 30 to 70% byweight of a pharmaceutically acceptable carrier, all percentages beingbased on the total composition.

The pharmaceutical composition may additionally contain various otheringredients known in the art, for example, a lubricant, stabilisingagent, buffering agent, emulsifying agent, viscosity-regulating agent,surfactant or preservative.

Pharmaceutical compositions comprising a compound of the invention infree form or in pharmaceutically acceptable salt form in associationwith at least one pharmaceutical acceptable carrier or diluent can bemanufactured in conventional manner by mixing with a pharmaceuticallyacceptable carrier or diluent and exhibit the same order of activity asthe free compounds.

The compounds of the invention may be administered alone or incombination with a second drug substance. To achieve higher efficacy andprevent the development of drug resistance, the compounds of theinvention may be combined with the following non-exhaustive list ofknown and marketed antimalarial drugs: artesunate, artemether,di-hydro-artemisinin, mefloquine, chloroquine, sulfadoxine,pyrimethamine, piperaquine, pyronaridine, lumefantrine or atovaquone.

Combinations include fixed combinations, in which a compound of theinvention and at least one second drug substance are in the sameformulation; kits, in which a compound of the invention and at least onesecond drug substance in separate formulations are provided in the samepackage, e.g. with instructions for co-administration; and freecombinations in which a compound of the invention and at least onesecond drug substance are packaged separately, but instructions forconcomitant or sequential administration are given.

Treatment with combinations according to the invention may provideimprovements compared with single treatment.

A combination of a compound of the invention and a second drug substanceas a combination partner may be administered by any conventional route,for example as set out herein for a compound of the invention. A seconddrug may be administered in dosages as appropriate, e.g. in dosageranges which are similar to those used for single treatment, or, e.g. incase of synergy, below conventional dosage ranges.

Pharmaceutical compositions comprising a combination of the inventionand pharmaceutical compositions comprising a second drug as describedherein, may be provided as appropriate, e.g. according, e.g.analogously, to a method as conventional, or as described herein for apharmaceutical composition of the invention.

The invention also provides a method for the preparation of a spirooxindole compound, the method including reacting an amine with anisatin.

In one embodiment, the method comprises reacting an indolylalkylaminewith a heterocyclic compound having a carbonyl group to form a spirocompound with an amine functional group; protecting the amine functionalgroup on the spiro compound with a protecting group to form anamine-protected spiro compound; and removing the protecting group fromthe spiro compound.

Through use of the protecting group, the overall yield of the synthesismay be increased and the purification process may be simplified (e.g.99% of compound 1 is obtainable with the method provided by theinvention using only flash column chromatography). The overall processis efficacious and amenable to large scale synthesis.

Spirocyclization may be effected in the presence of a catalyst such as,for example, pTsOH. Six-, seven-, or eight member rings with or withoutsubstituent analogues may be made by adjusting the quantity of catalystused. Further, the presence of the catalyst (e.g. about 0.1 to 0.2equivalent of pTsOH) accelerates the reaction and lowers the reactiontemperature to, for example, about 100° C.

It will be appreciated that the compounds of the invention may exist inthe form of optical isomers, racemates or diastereoisomers. The scope ofthis invention embraces all stereochemically isomeric forms of thecompounds. The term “stereogenic” forms” as used herein therefore meansall possible isomeric forms which the compounds of the invention maypossess. In particular, asymmetric carbons may have the R- orS-configuration. For example, the asymmetric sprio carbon of thecompounds of the invention may have the R- or S-configuration. Pureenantiomeric compounds may be obtained by eg obtention of theenantiomers from the racemates in conventional manner by chiralseparation, from chiral intermediates, or enzymatic resolution.

It will also be appreciated that the compounds of the invention canexist as tautomers. For example, compounds of the invention where R1 isOH or NH₂ or where R2 is NH₂ may exist as tautomeric forms. The scope ofthis invention embraces all such tautomeric forms.

In a group of compounds, the compounds comprise the following

a) compounds of the invention wherein the stereochemistry of the spirocarbon atom (with regard to the 4 bonds) is the same as that of Example50 hereinafter. In a sub-group one of R4 and R5 is a substitutent andthe other is hydrogen and the stereochemistry of the carbon atom towhich R4 and R5 are attached is the same as that of the Example 50 titlecompound hereinafter.

b) compounds of the invention wherein the stereochemistry of the spirocarbon atom is the opposite as that of Example 50 hereinafter. In asub-group one of R4 and R5 is a substitutent and the other is hydrogenand the stereochemistry of the carbon atom to which R4 and R5 areattached is the same as that of the Example 50 title compoundhereinafter.

c) compounds of the invention wherein the substituents on Spiro carbonatom may have any configuration. Conveniently the compounds of formula Imay have any configuration of the carbon atom to which R4 and R5 areattached.

A group of compounds comprises the title compounds of at least one ofthe example title compounds. In a sub-group the compounds are racemic.In a second subgroup the compounds have the same stereo-configuration atthe spiro carbon in Example 50. In a third subgroup the compounds havethe opposite stereo-configuration at the spiro carbon in Example 50.

Abbreviations

AcHN=acetamidoAcOH=acetic acidAloc=allyloxycarbonylBn=benzylBOC, Boc, t-BOC=tert-butoxycarbonyl(Boc)₂O=di-tert-butyl dicarbonateCbz=benzyloxycarbonylClCO₂Et=ethyl chloroformateDCM=dichloromethaneDMAP=dimethylaminopyridineDMF=dimethylformamideDMSO=dimethylsulfoxidedi-Cl=dichloroEDG=electron donating groupEt=ethylEt₃N=triethylamineEtOAc=ethyl acetateEtOH=ethanolFmoc=9-fluorenylmethoxycarbonyliPr=isopropylLC-MS=liquid chromatography-mass spectrometryMe=methylMeO=methoxyMeOH=methanolNaH=sodium hydride (60% paraffin)NH₄OAc=ammonium acetateNi(R)=Raney nickelNMe₂=dimethylaminoOPh=phenoxyOTs=tosylatePMB=p-methoxybenzylPr=propylpTsCl=p-toluenesulfonyl chloridepTsOH=p-toluenesulfonic acidrt=room temperatureTBS=t-butyldimethylsilylTHF=tetrahydrofuranTPDMS=t-butyldiphenylsilylTroc=2,2,2-trichloroethoxycarbonyl

I—General Synthetic Methods

Compounds of the invention can be made by the methods depicted in thereaction schemes shown below. The starting materials and reagents usedin preparing these compounds are either available commercially or areprepared by methods known to those skilled in the art. These schemes aremerely illustrative of some of the methods by which the compounds ofthis invention can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the arthaving referred to this disclosure.

To a solution of 4-(1H-indol-3-yl)-butan-2-one (1.0 g, 5.3 mmol) inmethanol (20 mL is added ammonium acetate (4.45 g, 57.73 mmol) andsodium cyanoborohydride (0.37 g, 5.9 mmol) at room temperature. Theresulting mixture is allowed to stir for 64 hours at the sametemperature. The reaction mixture is quenched by addition of 1 Nhydrochloric acid and adjusted to pH ˜2. The mixture is concentrated andextracted with dichloromethane (50 mL). Then the aqueous phase isadjusted to pH ˜12 using 4 N aqueous sodium hydroxide and extracted withdichloromethane (3×50 mL). The combined organic phases are dried withsodium sulfate and concentrated in vacuo. The resulting residue issubjected to flash column chromatography (5%-30% methanol indichloromethane) to afford 3-(1H-indol-3-yl)-1-methyl-propylamine (622mg, 62%) as an oil.

Step 1: To a solution of 3-(1H-indol-3-yl)propanoic acid (6.06 g, 32.0mmol) in tetrahydrofuran (100 mL) is added triethylamine (18 mL, 129mmol) and ethyl chloroformate (4.65 mL, 48.8 mmol) in an ice cooledbath. The resulting mixture is allowed to stir for 0.5 hours at the sametemperature followed by the addition of ammonia (2 N in methanol, 90 mL,180 mmol). After stirring for a further one hour, the resultingprecipitate is filtered off and the filtrate is concentrated in vacuo.The residue, after diluted with water (100 mL), is extracted with ethylacetate (3×100 mL). The combined organic phases are washed with brine,dried with sodium sulfate and concentrated in vacuo to obtain3-(1H-indol-3-yl)propylamide (3.85 g, 65%).

Step 2: To the solution of 3-(1H-indol-3-yl)propylamide (1.85 g, 9.83mmol) in tetrahydrofuran (50 mL) is added lithium aluminum hydride (1.49g, 39.31 mmol) at 0° C. The resulting mixture is warmed to roomtemperature and then refluxed for 2.5 hours. The mixture is then cooledto room temperature and quenched by slow addition of water (2 mL)followed by aqueous 15% sodium hydroxide (2 mL) and water (2 mL). Themixture is allowed to stir overnight and filtered through celite. Thefiltrate obtained is evaporated and the residue is subjected to flashcolumn chromatography (50% dichloromethane: 40% methanol: 10% aqueousammonia (40%)) to afford 3-(1H-Indol-3-yl)propylamine (1.61 g, 94%).

Step 1: To a solution of 3-(1H-indol-3-yl)-1-methyl-propylamine (1.84 g,4.65 mmol) in 20 mL of ethanol is added 5-bromoisatin (660 mg, 2.92mmol) and p-toluenesulfonic acid (101 mg, 0.531 mmol) at roomtemperature. The reaction vial is sealed and the reaction mixture isheated to 100° C. After stirring for 16 hours, the reaction mixture iscooled to room temperature and concentrated to dryness. The residue issubjected to flash column chromatography (0%-30% EtOAc in hexanes) toafford the impure 1 as dark brown solid (2.74 g).

Step 2: To a solution of the above product (2.74 g, 6.91 mmol) in 13 mLof dry dichloromethane is added triethylamine (2.87 mL, 20.73 mmol),followed by di-tert-butyl dicarbonate (9.05 g, 41.46 mmol) and4-dimethylaminopyridine (2.53 g, 20.7 mmol) at room temperature. Theresulting mixture is stirred for 16 hours at the same temperature andthen concentrated to dryness. The residue is subjected to flash columnchromatography (0%-4% EtOAc in hexanes) to afford 2.22 g of compound 12.

Step 3: To a solution of obtained compound 12 (2.2 g, 3.72 mmol) inanhydrous dichloromethane (10 mL) is added 4 N HCl in 1,4-dioxane (15mL). The resulting mixture is stirred for 48 hours, during which timeanother batch of 4 N HCl in dioxane is added to ensure the reaction iscompleted. After the reaction, monitored by LCMS, is completed, thereaction mixture is adjusted to pH ˜10 using aqueous 1 N NaOH. Themixture is concentrated in vacuo and the remaining aqueous phase isextracted with EtOAc (3×100 mL). The combined organic phases are dried(Na₂SO₄) and concentrated in vacuo. The residue is subjected to flashcolumn chromatography to afford compound 1 (1.28 g, 37% over 3 steps)along with a trace amount of compound 13 (30 mg).

Step 1: A mixture of 5-methoxygramine (3.0 g, 14.7 mmol), 2-nitropropane(9.36 mL, 104 mmol) and NaOH pellets (0.617 g, 15.4 mmol) is stirred andheated at reflux for 18 hours. After the mixture is cooled to roomtemperature, 12.85 mL of 10% acetic acid is added and stirring iscontinued for one hour. The mixture is partitioned between diethyl ether(40 mL) and water (40 mL) and the organic layer is separated, washedwith water (3×30 mL), dried over MgSO₄ and concentrated in vacuo. Theresidue is subjected to flash chromatography column to give a nitrointermediate (3.12 g, 86%).

Step 2: To a solution of the nitro intermediate (3.12 g, 12.6 mmol) in40 mL of 95% EtOH is added, with stirring, 2.0 g of Raney nickel. Themixture is heated to 80° C. and then stopped. A solution of 98%hydrazine hydrate (2.8 mL, 0.0377 mol) in 3.3 mL EtOH is added at a ratesufficient to maintain reflux throughout the addition. Heat is reappliedto continue reflux overnight. The mixture is filtered and the filtrateconcentrated in vacuo. The residue was precipitated from dilute aqueousHCl solution with 4 N NaOH, extracted with dichloromethane, andrecrystallized from isopropanol to give amine (1.92 g, 70% yield).

Step 3: To a mixture of the above amine (1.2 g, 5.5 mmol) and5-chloroisatin (1.10 g, 6.05 mmol) in 20 mL of ethanol was addedp-toluenesulfonic acid (0.209 g, 5.5 mmol). The reaction vial was sealedand heated to 130° C. for 16 hours. The target compound precipitatedupon cooling. The solids are filtered and washed several times with(ice) cold ethanol to yield compound 31 (1.29 g, 62%).

To a mixture of 2-chloroaniline (1.02 g, 7.84 mmol), anhydrous sodiumsulfate (8.94 g, 62.71 mmol), hydroxylamine hydrochloride (2.24 g, 31.35mmol) and 1M hydrochloric acid (8.0 mL) in water (60 mL) is addedchloral hydrate (1.58 g, 9.41 mmol) at room temperature. The resultingmixture is warmed to 55° C. and stirred for 6 hours. While the mixtureis cooling to room temperature, solid precipitate is formed andcollected by filtration, washed with water and dried under vacuum toyield the hydroxyliminoacetanilide intermediate, which is added in smallportions to concentrated sulfuric acid (5.0 mL) that is preheated to 55°C. The temperature of the reaction mixture is maintained at below 58° C.throughout the addition. After the addition is completed, thedark-colored mixture is heated to 80° C. for 10 minutes before coolingdown to room temperature. The mixture is then poured into crushed ice,swirled, and left to stand for 30 minutes. The precipitate formed iscollected by filtration, washed with water and dried under vacuum toyield 7-chloroisatin as a reddish brown powder.

Step 1: To a mixture of D-tryptophanol (500 mg, 2.27 mmol) in 11.3 mLwater and 11.3 mL acetone is added sodium carbonate (482 mg, 3.92 mmol)in an ice cooled bath, followed by dropwise addition of benzylchloroformate (0.374 mL, 2.29 mmol). After the addition, the coolingbath is removed and the reaction is stirred at room temperature for 2hours. The reaction mixture is acidified to pH 2 with concentrated HCland diluted with water (40 mL). The aqueous layer is extracted withEtOAc (2×60 mL). The combined organics are then dried with magnesiumsulfate, filtered and concentrated in vacuo. The residue is subjected toflash chromatography column to give a Cbz protected intermediate (428mg, 50%).

Step 2: A solution of the Cbz-protected intermediate (320 mg, 0.988mmol) and triethylamine (267 μL, 1.93 mmol) in dry dichloromethane (2.78mL) is cooled to 0° C. p-Toluenesulfonyl chloride (199.6 mg, 1.05 mmol)is added and the solution is stirred at room temperature for 18 hours.The reaction mixture is concentrated in vacuo. The residue is subjectedto flash chromatography column to give the corresponding tosylate (580mg, 100%).

Step 3: The tosylate intermediate (580 mg, 1.21 mmol) is dissolved in 36mL absolute ethanol and 72.7 mg palladium (II) hydroxide catalyst isadded. The reaction mixture is stirred under 1 atm H₂ atmosphere at roomtemperature for 2 hours. The reaction mixture is filtered through celiteand the filtration is concentrated in vacuo. The residue is dissolved inEtOAc (50 mL), washed with sat aq NaHCO₃ (50 mL, dried with magnesiumsulfate, filtered and concentrated in vacuo to yield the S-amine (169mg, 80%).

Step 4: To a stirring solution of the S-indoleamine (153 mg, 0.881 mmol)in 3.1 mL dry ethanol is added 5-chloroisatin (176 mg, 0.969 mmol) andp-toluenesulfonic acid (16.8 mg, 0.088 mmol). The solution is stirred at110° C. for 16 hours in a sealed tube. The reaction mixture isconcentrated in vacuo. The residue is subjected to flash chromatographycolumn and further purified by precipitation using petroleum ether togive compound 33 (135 mg, 45%).

Step 1: POCl₃ (2.43 mL, 26.53 mmol) was added dropwise toN,N-dimethylformamide (15.0 mL) at −20° C. and stirred below −5° C. forone hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) indimethylformamide (5.0 mL) was added dropwise to the above reactionmixture at −20° C. The salt-ice bath was removed and the reactionmixture was warmed to 35° C., After one hour, the reaction was pouredonto ice and basified by solid sodium bicarbonate and extracted withethyl acetate. The combined organic layer was washed with water and thenconcentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g,97%) as a light brown solid. ¹H NMR (500 MHz, CDCl₃): δ 10.02 (s, 1H),8.10 (d, 1H, J=9.5 Hz), 7.87 (s, 1H), 7.49 (d, 1H, J=5.5 Hz).

Step 2: The solution (0.2 M) of6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.0 g, 20.24 mmol) innitroethane (100 mL) was refluxed with ammonium acetate (1.32 g, 0.85mmol) for 4 hours. The reaction mixture was concentrated under vacuum toremove nitroethane, diluted with ethylacetate and washed with brine. Theorganic layer was concentrated to give6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 97%) as areddish orange solid. ¹H NMR (500 MHz, CDCl₃): δ 8.77 (s, 1H), 8.32 (s,1H), 7.58 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=5.9Hz), 2.52 (s, 3H).

Step 3: A solution of 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole(5.0 g, 19.63 mmol) in tetrahydrofuran (10 mL) was added to thesuspension of lithium aluminium hydride (2.92 g, 78.54 mmol) intetrahydrofuran (20 mL) at 0° C. and then refluxed for 3 hours. Thereaction mixture was cooled to 0° C., and quenched according to theFischer method. The reaction mixture was filtered through celite and thefiltrate concentrated to give2-(6-chloro-5-fluoro-1H-indol-3-yl-1-methyl-ethylamine (4.7 g crude) asa viscous brown liquid. The residue was used without furtherpurification. ¹H NMR (500 MHz, CDCl₃): δ 8.13 (s, 1H), 7.37 (d, 1H, 6Hz), 7.32 (d, 1H, J=10 Hz), 7.08 (s, 1H), 3.23-3.26 (m, 1H), 2.77-2.81(m, 1H), 2.58-2.63 (m, 1H), 1.15 (d, 3H, J=6.5 Hz).

Step 4: A mixture of2-(6-chloro-5-fluoro-1H-indol-3-yl-1-methyl-ethylamine (4.7 g, 20.73mmol), 5-chloroisatin (3.76 g, 20.73 mmol) and p-toluenesulphonic acid(394 mg, 2.07 mmol) in ethanol (75 mL) was refluxed overnight. Thereaction mixture was concentrated to remove ethanol, diluted with ethylacetate and washed with saturated aqueous NaHCO₃. The organic layer wasconcentrated to give a brown residue, which was purified by silica gelchromatography (20% ethyl acetate in hexane) to provide thecorresponding racemate (4.5 g, 56%) as a light yellow solid. Theracemate was separated into its enantiomers by chiral chromatography toprovide 35.

Compound 36 can be obtained in a similar fashion from 5-fluoroindole.

Alternatively 35 and 36 were be prepared in enantiomerically pure formby the following scheme.

Step 1: To a solution of 6-chloro-5-fluoroindole (1.8 g, 10.8 mmol) andAc₂O (10 mL) in AcOH (30 mL) was added L-serine (2.2 g, 20.9 mmol), themixture was heated to 80° C. After TLC indicated the reaction wascomplete, the mixture was cooled to 0° C., neutralized to pH 11, andwashed with MTBE. The aqueous phase was acidified to pH 2 and extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried with Na₂SO₄, filtered, and concentrated. The residue waspurified with chromatography (Petroleum ether/EtOAc 1:1) to give2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid as alight yellow solid (1.2 g, 37% yield).

Step 2: 2-Acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionicacid (2.5 g, 8.4 mmol) was dissolved in aqueous NAOH (1N, 10 mL) andwater added (70 mL). The mixture was heated to 37-38° C. and neutralizedwith HCl (1N) to pH 7.3-7.8. L-Aminoacylase (0.5 g) was added to themixture and allowed to stir for 2 days, maintaining 37-38° C. and pH7.3-7.8. The mixture was heated to 60° C. for another hour, concentratedto remove part of water, cooled and filtered. The filtrate was adjustedto pH 5.89 and filtered again. The filtrate was adjusted to pH 2.0 andextracted with EtOAc. The combined organic layer was dried over Na₂SO₄,filtered, concentrated and the residue was purified with chromatography(petroleum ether/EtOAc 1:1 EtOAc) to giveR-2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid as alight yellow solid (1.2 g, 48% yield).

Step 3: R-2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionicacid (1.2 g, 4.0 mmol) was dissolved in HCl (6N, 10 mL) and the mixtureheated to reflux for 4 hours, and then concentrated to dryness. Toluene(50 mL) was added to the residue and concentrated to dryness to removewater and HCl. The residue was dried under vacuum and then dissolved inMeOH (20 mL). To the solution was added dropwise SOCl₂ (0.5 mL, 6.8mmol) at 0° C., and the mixture was stirred overnight. After removal ofsolvent, the residue was dissolved in THF/water (40/10 mL) and NaHCO₃(1.0 g, 11.9 mmol) was added portionwise. Upon basification, Boc₂O (1.2g, 5.5 mmol) added at 0° C. and allowed to stir at room temperature.After TLC indicated the reaction was finished, EtOAc was added andseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried with Na₂SO₄,filtered, concentrated and the residue was purified with chromatography(petroleum ether/EtOAc: 5/1) to giveR-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionicacid methyl ester 460 g, 31% yield for 3 steps).

Step 4: To a solution ofR-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionicacid methyl ester (460 mg, 1.2 mmol) in dry ether (20 mL) was addedportionwise LiAlH₄ (92 mg, 2.4 mmol) at 0° C. The mixture was heated toreflux for 2 hours. After TLC indicated the reaction was finished, themixture was cooled and carefully quenched with Na₂SO₄. The mixture wasfiltered and the filtrate was washed with saturated aqueous NH₄Cl andwater, dried with Na₂SO₄, filtered, concentrated to give a crude product(400 mg), which was used without further purification.

Step 5: To a solution of the crude product (400 mg, 1.2 mmol) and Et₃N(0.3 mL, 2.2 mmol) in CH₂Cl₂ (5 mL) was added MsCl (160 mg, 1.4 mmol)dropwise at 0° C. The mixture was stirred for 2 hours at roomtemperature. After TLC indicated the reaction was completed, the mixturewas washed with water and brine, dried with Na₂SO₄, filtered,concentrated and the residue was purified with chromatography (petroleumether/EtOAc 5:1) to give methansulfonic acid(R)-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-propylester as a light yellow solid (300 mg, 57% yield, 2 steps)

Step 6: To a solution of mesylate (300 mg, 0.7 mmol) in dry ether (20mL) was added portionwise LiAlH₄ (55 mg, 1.4 mmol) at 0° C. The mixturewas stirred at room temperature overnight. After TLC indicated thereaction was finished, the mixture was cooled and carefully quenchedwith Na₂SO₄. The mixture was filtered and the filtrate was washed withsaturated aqueous NH₄Cl and water, dried with Na₂SO₄, filtered,concentrated and the residue was purified with chromatography (petroleumether/EtOAc 10:1) to give[(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-carbamic acidtert-butyl ester as a light yellow solid (200 mg, 87% yield).

Step 7: A solution of[(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-carbamic acidtert-butyl ester (200 mg, 0.6 mmol) in HCl/MeOH (10 mL) was stirred atroom temperature. After TLC indicated the reaction was finished, themixture was concentrated to remove the solvent. To the residue was addedEtOAc (50 mL), and the mixture was neutralized with saturated NaHCO₃ topH 8-9, and then extracted with EtOAc. The combined organic phases weredried with Na₂SO₄, filtered, concentrated to give a crude(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine which wasused without further purification.

Step 8: To a solution of(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine (120 mg, 0.5mmol) in EtOH (10 mL) was added 5-chloroisatin (90 mg, 0.5 mmol) andp-TsOH (8 mg, 0.04 mmol). The mixture was heated in a sealed tube at110° C. for 16 hours. After TLC indicated the reaction was finished, themixture was cooled and concentrated. The residue was dissolved in EtOAc(20 mL) and washed with NaOH (1N) and brine, dried with Na₂SO₄,filtered, concentrated and the residue was purified with chromatography(petroleum ether/EtOAc 5:1) to give 36 (150 mg, 64% yield over twosteps).

EXAMPLES

The invention is described with reference to the following examples. Itis to be appreciated that the invention is not limited to theseexamples. Where not otherwise designated the compounds of the inventionare in free base form.

Example 1 3-(1H-Indol-3-yl)-1-methyl-propylamine

The title compound may be prepared from 4-(1H-indol-3-yl)-butan-2-oneaccording to Scheme A.

3-(1H-Indol-3-yl)-1-methyl-propylamine: ¹H NMR (300 MHz, DMSO-d₆): δ10.71 (s, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.08 (d,J=2.1 Hz, 1H), 7.04 (td, J=8.1, 1.5 Hz, 1H), 6.95 (td, J=7.2, 1.2 Hz,1H), 2.81 (m, 1H), 2.70 (m, 2H), 1.61 (m, 2H), 1.02 (d, J=6.3 Hz, 3H);MS (ESI) m/z 189.0 (M+H⁺).

Example 2 2-(1H-Indol-3-yl)-1-methyl-ethylamine

The title compound may be prepared according to Scheme A using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

2-(1H-Indol-3-yl)-1-methyl-ethylamine: ¹H NMR (300 MHz, DMSO-d₆): δ10.79 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.33 (dd, J=7.8, 0.9 Hz, 1H),7.11 (d, J=2.1 Hz, 1H), 7.04 (td, J=7.8, 1.2 Hz, 1H), 6.95 (td, J=6.9,0.9 Hz, 1H), 3.07 (m, 1H), 2.62 (m, 2H), 0.98 (d, J=6.3 Hz, 3H); MS(ESI) m/z 175.0 (M+H⁺).

Example 3 3-(1H-Indol-3-yl)propylamide

The title compound may be prepared from 3-(1H-indol-3-yl)propanoic acidaccording to Step 1 of Scheme B.

3-(1H-Indol-3-yl)propylamide: ¹H NMR (300 MHz, DMSO-d₆): δ 10.73 (s,1H), 7.52 (d, J=9 Hz, 1H), 7.32 (dt, J=7.8 Hz, 0.9 Hz, 1H), 7.29 (s,1H), 7.09-6.94 (m, 3H), 6.73 (s, 1H), 2.90 (t, J=8.1 Hz, 2H), 2.41 (t,J=7.5 Hz, 2H); MS (ESI) m/z 189.0 (M+H⁺).

Example 4 3-(1H-Indol-3-yl)-propylamine

The title compound may be prepared from 3-(1H-indol-3-yl)propanoic acidaccording to Scheme B.

3-(1H-Indol-3-yl)propylamine: ¹H NMR (300 MHz, DMSO-d₆): δ 10.71 (s,1H), 7.50 (d, J=7.5 Hz, 1H), 7.32 (td, J=8.4, 0.9 Hz, 1H), 7.08 (d,J=1.8 Hz, 1H), 7.04 (td, J=8.1, 1.2 Hz, 1H), 6.95 (td, J=7.2, 0.9 Hz,1H), 2.69 (m, 2H), 2.59 (m, 2H), 1.71 (m, 2H); MS (ESI) m/z 175.0(M+H⁺).

Example 5 [3-(1H-Indol-3-yl)-propyl]-methyl-amine

The title compound may be prepared according to Scheme B using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

[3-(1H-Indol-3-yl)-propyl]-methyl-amine: ¹H NMR (300 MHz, DMSO-d₆): δ10.72 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.08 (d,J=2.1 Hz, 1H), 7.04 (td, J=6.9, 1.2 Hz, 1H), 6.95 (td, J=6.9, 1.2 Hz,1H), 2.69 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.28 (s, 3H), 1.76(m, 2H); MS (ESI) m/z 189.0 (M+H⁺).

Example 6 4-(1H-Indol-3-yl)-butylamine

The title compound may be prepared according to Scheme B using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

4-(1H-Indol-3-yl)-butylamine: ¹H NMR (300 MHz, DMSO-d₆): δ 10.71 (s,1H), 7.49 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.08 (d, J=2.1 Hz,1H), 7.04 (td, J=7.8, 1.2 Hz, 1H), 6.95 (td, J=7.8, 1.2 Hz, 1H), 2.67(t, J=7.5 Hz, 2H), 2.56 (t, J=6.9 Hz, 2H), 1.65 (m, 2H), 1.41 (m, 2H);MS (ESI) m/z 189.0 (M+H⁺).

Example 75′-Bromo-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(1)

Compound 1 may be prepared from 3-(1H-indol-3-yl)-1-methyl-propylamineaccording to Scheme C.

5′-Bromo-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (600 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.98 (s, 1H), 8.14 (s, 1H),7.46 (d, J=8.4 Hz, 2H), 7.26 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.70 (t,J=7.2 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 3.89 (bs,1H), 3.11 (m, 1H), 2.87 (m, 1H), 2.07 (m, 1H), 1.65 (m, 1H), 1.05 (d,J=6.6 Hz, 3H); MS (ESI) m/z 397.0 (M+H⁺).

Example 85′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(2)

Compound 2 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.95 (s, 1H), 8.25 (s, 1H),7.46 (dd, J=6.6, 1.8 Hz, 1H), 7.32 (dd, J=8.1, 2.4 Hz, 1H), 7.16 (m,2H), 6.96 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 3.89 (m, 1H), 3.11 (m, 1H),2.86 (m, 1H), 2.07 (m, 1H), 1.64 (m, 1H), 1.04 (d, J=6.6 Hz, 3H); MS(ESI) m/z 352.0 (M+H⁺).

Example 95′-Fluoro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(3)

Compound 3 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Fluoro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.32 (s, 1H), 9.91 (s, 1H), 8.14 (s, 1H),7.45 (dd, J=6.6, 1.8 Hz, 1H), 7.19-7.06 (m, 2H), 7.03-6.90 (m, 3H), 6.88(dd, J=8.7, 4.2 Hz, 1H), 3.92 (m, 1H), 3.13 (m, 1H), 2.88 (m, 1H), 2.07(m, 1H), 1.63 (m, 1H), 1.05 (d, J=6.9 Hz, 3H); MS (ESI) m/z 336.0(M+H⁺).

Example 103-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(4)

Compound 4 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

3-Methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.50 (s, 1H), 8.31 (s, 1H),7.50 (d, J=7.2 Hz, 1H), 7.25-7.16 (m, 2H), 7.00-6.81 (m, 5H), 4.16-4.07(m, 1H), 2.78-2.53 (m, 2H), 1.94-1.75 (m, 2H), 1.33 (d, J=6.0 Hz, 3H)ppm; MS (ESI) m/z 318.0 (M+H⁺).

Example 115′-Bromo-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one (5)

Compound 5 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Bromo-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one: ¹HNMR (300 MHz, DMSO-d₆): δ 10.56 (s, 1H), 10.47 (s, 1H), 8.17 (s, 1H),7.44 (m, 2H), 7.18 (s, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.00 (m, 2H), 6.89(d, J=8.4 Hz, 1H), 3.57 (m, 1H), 3.09 (m, 1H), 2.76 (m, 2H); MS (ESI)m/z 369.0 (M+H⁺).

Example 125′-Chloro-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(6)

Compound 6 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Chloro-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.57 (s, 1H), 10.48 (s, 1H), 7.47 (d,J=7.2 Hz, 1H), 7.32 (dd, J=8.1, 2.1 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H),7.09 (d, J=2.1 Hz, 1H), 7.02 (m, 2H), 6.95 (d, J=8.1 Hz, 1H), 3.59 (m,1H), 3.12 (m, 2H), 2.80 (m, 1H); MS (ESI) m/z 324.0 (M+H⁺).

Example 135′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one(7)

Compound 7 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 10.42 (s, 1H), 7.43 (d,J=7.2 Hz, 1H), 7.31 (dd, J=8.4, 2.4 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),7.03 (d, J=2.4 Hz, 1H), 6.99 (m, 1H), 6.92 (d, J=8.4 Hz, 2H), 3.93 (m,1H), 3.05 (d, J=6.3 Hz, 1H), 2.79 (dd, J=15.0, 3.6 Hz, 1H), 2.41 (dd,J=15.0, 10.5 Hz, 1H), 1.18 (d, J=6.3 Hz, 3H); MS (ESI) m/z 338.0 (M+H⁺).

Example 145′-Bromo-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(8)

Compound 8 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Bromo-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.58 (bs, 1H), 10.11 (s, 1H), 7.46 (m,2H), 7.26 (d, J=2.1 Hz, 1H), 7.16 (dd, J=6.6, 1.2 Hz, 1H), 6.97 (m, 2H),6.89 (d, J=8.4 Hz, 1H), 3.46 (m, 1H), 3.01 (m, 3H), 1.98 (m, 2H); MS(ESI) m/z 383.0 (M+H⁺).

Example 155′-Chloro-2,3,4,5,6,11-hexahydrospiro[azocino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(9)

Compound 9 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Chloro-2,3,4,5,6,11-hexahydrospiro[azocino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.54 (s, 1H), 8.45 (bs, 1H), 7.47 (d,J=7.8 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.33 (m, 2H), 7.05 (m, 2H), 6.96(m, 1H), 2.54 (m, 1H), 2.40 (m, 3H), 1.39 (m, 4H); MS (ESI) m/z 352.0(M+H⁺).

Example 161′-Benzyl-5′-chloro-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(10)

Compound 10 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

1′-Benzyl-5′-chloro-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.13 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.34(m, 5H), 7.29 (m, 1H), 7.25 (d, J=2.1 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H),6.99 (m, 3H), 4.92 (dd, J=77.1, 16.2 Hz, 2H), 3.51 (m, 1H), 3.07 (m,3H), 2.02 (m, 2H); MS (ESI) m/z 429.0 (M+H⁺).

Example 17(1S,3S)-5′-Chloro-3-(hydroxymethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(11)

Compound 11 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

(1S,3S)-5′-Chloro-3-(hydroxymethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.49 (s, 1H), 10.45 (s, 1H), 7.45 (d,J=6.9 Hz, 1H), 7.33 (dd, J=8.1, 2.1 Hz, 1H), 7.17 (m, 1H), 7.07-6.91 (m,4H), 4.65 (t, J=5.4 Hz, 1H), 3.92 (m, 1H), 3.50 (t, J=5.4 Hz, 1H), 2.89(m, 1H), 2.80 (dd, J=15.0, 3.6 Hz, 1H), 2.44 (m, 1H); MS (ESI) m/z 354.0(M+H⁺).

Example 18 Di-tert-butyl5′-bromo-3-methyl-2′-oxo-4,5-dihydro-2H-spiro[azepino[3,4-b]indole-1,3′-indole]-1′,10(2′H,3H)-dicarboxylate (12)

Compound 12 may be prepared according to Steps 1 and 2 of Scheme C.

Di-tert-butyl5′-bromo-3-methyl-2′-oxo-4,5-dihydro-2H-spiro[azepino[3,4-b]indole-1,3′-indole]-1′,10(2′H,3H)-dicarboxylate: ¹H NMR (300 MHz, DMSO-d₆): δ 7.71 (m, 3H), 7.51 (dd,J=8.6, 2.1 Hz, 1H), 7.30 (m, 2H), 6.99 (d, J=2.1 Hz, 1H), 3.10 (m, 2H),2.87 (m, 1H), 2.16 (m, 1H), 1.63 (m, 1H), 1.57 (s, 9H), 1.33 (s, 9H),1.00 (d, J=6.6 Hz, 3H); MS (ESI) m/z 597.0 (M+H⁺).

Example 19 tert-Butyl5′-bromo-3-methyl-2′-oxo-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indole]-1′(2′H)-carboxylate(13)

Compound 13 may be prepared according to Scheme C.

tert-Butyl5′-bromo-3-methyl-2′-oxo-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indole]-1′(2′H)-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.33 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.64(d, J=7.2 Hz, 1H), 7.28 (m, 3H), 6.83 (d, J=2.1 Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 3.47 (m, 1H), 2.97 (m, 1H), 2.82 (m, 1H), 2.37 (m, 1H), 1.65(m, 1H), 1.30 (s, 9H), 1.02 (d, J=6.6 Hz, 3H); MS (ESI) m/z 497.0(M+H⁺).

Example 20 Methyl(1S,3S)-5′-bromo-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate(14)

Compound 14 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

Methyl(1S,3S)-5′-bromo-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.60 (s, 1H), 10.54 (s, 1H), 7.50-7.46 (m,2H), 7.28 (d, J=2.1 Hz, 1H), 7.18 (d J=7.8 Hz, 1H), 7.08-6.96 (m, 2H),6.90 (d, J=8.1 Hz, 1H), 4.73-4.66 (m, 1H), 3.71 (s, 3H), 3.51 (d, J=7.2Hz, 1H), 3.08 (dd, J=3.9, 15.0 Hz, 1H), 2.88 (dd, J=11.1, 15.2 Hz, 1H);MS (ESI) m/z 427.0 (M+H)⁺.

Example 21 Ethyl(1S,3S)-5′-bromo-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate(15)

Compound 15 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

Ethyl(1S,3S)-5′-bromo-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 10.54 (s, 1H), 7.50-7.46 (m,2H), 7.29 (d, J=2.1 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.08-6.96 (m, 2H),6.90 (d, J=8.1 Hz, 1H), 4.70-4.63 (m, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.47(d, J=6.9 Hz, 1H), 3.08 (dd, J=4.2, 15.0 Hz, 1H), 2.87 (dd, J=11.1, 15.0Hz, 1H), 1.26 (t, J=6.9 Hz, 3H); MS (ESI) m/z 441.0 (M+H)⁺.

Example 22 Methyl(1S,3R)-5′-chloro-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate(16)

Compound 16 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

Methyl(1S,3R)-5′-chloro-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 10.54 (s, 1H), 7.50-7.46 (m,2H), 7.28 (d, J=2.1 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.08-6.96 (m, 2H),6.90 (d, J=8.4 Hz, 1H), 4.73-4.66 (m, 1H), 3.71 (s, 3H), 3.51 (d, J=6.9Hz, 1H), 3.08 (dd, J=3.9, 15.0 Hz, 1H), 2.88 (dd, J=11.1, 15.3 Hz, 1H);MS (ESI) m/z 427.0 (M+H)⁺.

Example 23 Ethyl(1S,3R)-5′-chloro-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate(17)

Compound 17 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

Ethyl(1S,3R)-5′-chloro-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-3-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 10.54 (s, 1H), 7.50-7.46 (m,2H), 7.29 (d, J=1.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.08-6.96 (m, 2H),6.90 (d, J=8.1 Hz, 1H), 4.70-4.63 (m, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.47(d, J=6.9 Hz, 1H), 3.07 (dd, J=4.5, 15.2 Hz, 1H), 2.87 (dd, J=11.1, 15.0Hz, 1H), 1.26 (t, J=7.2 Hz, 3H) ppm; MS (ESI) m/z 441.0 (M+H)⁺.

Example 24(1S,3R)-5′-Chloro-3-(hydroxymethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(18)

Compound 18 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

(1S,3R)-5′-Chloro-3-(hydroxymethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.49 (s, 1H), 10.45 (s, 1H), 7.45 (d,J=6.9 Hz, 1H), 7.32 (dd, J=2.1, 8.3 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H),7.06-6.92 (m, 4H), 4.64 (t, J=6.0 Hz, 1H), 3.95-3.86 (m, 1H), 3.49 (t,J=5.7 Hz, 1H), 2.90 (d, J=6 Hz, 1H), 2.80 (dd, J=3.9, 14.9 Hz, 1H),2.45-2.40 (m, 1H); MS (ESI) m/z 354.0 (M+H)⁺

Example 255′-Bromo-1′,3-dimethyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′-one(19)

Compound 19 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

5′-Bromo-1′,3-dimethyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′-one:¹H NMR (300 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.56 (dd, J=2.1, 8.6 Hz, 1H),7.48-7.45 (m, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.16-7.13 (m, 1H), 7.07 (d,J=8.4 Hz, 1H) 7.02-6.92 (m, 2H), 3.93-3.85 (m, 1H), 3.21-3.12 (m, 4H),2.93-2.84 (m, 2H), 2.11-1.99 (m, 1H), 1.71-1.59 (m, 1H), 1.03 (d, J=6.9Hz, 3H); MS (ESI) m/z 413.0 (M+H)⁺

Example 26(4S,6S)-5′-chloro-6-(hydroxymethyl)-3,5,6,7-tetrahydrospiro[imidazo[4,5-c]pyridine-4,3′-indol]-2′(1′H)-one(20)

Compound 20 may be prepared according to Scheme C using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

(4S,6S)-5′-chloro-6-(hydroxymethyl)-3,5,6,7-tetrahydrospiro[imidazo[4,5-c]pyridine-4,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, CD₃OD-d₄): δ 8.23 (s, 1H), 7.54 (s, 1H), 7.28 (dd,J=8.4 Hz, J=2.1 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.92 (d, J=9 Hz, 1H),4.16 (m, 1H), 3.65 (m, 2H), 2.79 (dd, J=15.3 Hz, J=4.2 Hz, 1H), 2.61 (m,1H); MS (ESI) m/z (M+H)⁺.

Example 27tert-Butyl-5′-bromo-3-methyl-2′-oxo-1′,2,2′,3,4,5-hexahydro-10H-spiro[azepino[3,4-b]indole-1,3′-indole]-10-carboxylate(21)

To a solution of compound 1 (10 mg, 0.025 mmol) in dry dichloromethane(0.3 mL) is added triethylamine (7.0 μL, 0.05 mmol) and di-tert-butyldicarbonate (5.51 mg, 0.025 mmol). The resulting mixture is stirred for60 hours at room temperature under argon atmosphere and thenconcentrated to dryness. The residue is subjected to flash columnchromatography (silica gel, hexanes:EtOAc, 20:1) to afford compound 21(3.3 mg, 44%) as white solid.

tert-Butyl-5′-bromo-3-methyl-2′-oxo-1′,2,2′,3,4,5-hexahydro-10H-spiro[azepino[3,4-b]indole-1,3′-indole]-10-carboxylate:¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.62(dd, J=8.7, 2.1 Hz, 1H), 7.49 (d, J=6.9 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H),7.15 (d, J=9.0 Hz, 1H), 6.99 (m, 2H), 3.78 (m, 1H), 3.15 (m, 1H), 2.86(m, 1H), 2.03 (m, 1H), 1.65 (m, 1H), 1.57 (s, 9H), 1.05 (d, J=6.6 Hz,3H) ppm; MS (ESI) m/z 497.0 (M+H⁺).

Example 285′-Bromo-1′,3,10-trimethyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(22)

To a solution of compound 1 (15 mg, 0.038 mmol) in dry DMF (0.4 mL)under argon atmosphere is added NaH (5.3 mg, 0.133 mmol) at roomtemperature. The solution becomes dark red as it is stirred for 30minutes at room temperature. Todomethane (9.43 μL, 0.152 mmol) is thenadded to the reaction mixture and the mixture is stirred for a furtherone hour at room temperature. The reaction mixture is then concentratedto dryness and water (10 mL) is added. The aqueous layer is extractedwith EtOAc (3×15 mL). The combined organic phases are washed with brine(20 mL), dried (Na₂SO₄) and concentrated in vacuo. The residue issubjected to flash column chromatography (silica gel, hexanes:EtOAc,8:2) to afford compound 22 (10.3 mg, 64%) as white solid.

5′-Bromo-1′,3,10-trimethyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 7.57 (m, 2H), 7.25 (d, J=7.8 Hz, 1H),7.16-6.98 (m, 4H), 3.74 (m, 1H), 3.24 (s, 3H), 3.01 (d, J=5.7 Hz, 1H),2.96 (s, 3H), 2.88 (m, 1H), 2.02 (m, 1H), 1.63 (m, 1), 1.00 (d, J=6.6Hz, 3H); MS (ESI) m/z 425.0 (M+H⁺).

Example 295′-Bromo-10-[(3-bromophenyl)carbonyl]-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino-[3,4-b]indole-1,3′-indol]-2′(1′H)-one(23)

To a solution of compound 1 (30 mg, 0.076 mmol) in dry dichloromethane(0.8 mL) is added triethylamine (31.48 μL, 0.228 mmol), 3-bromo-benzoylchloride (59.8 μL, 0.456 mmol) and 4-dimethylaminopyridine (13.9 mg,0.114 mmol). The resulting mixture is stirred for 16 hours at roomtemperature and then concentrated to dryness. The residue is subjectedto flash column chromatography (silica gel, 0%-10% EtOAc in hexanes) toafford compound 23 (15.3 mg, 37%) as white solid.

5′-Bromo-10-[(3-bromophenyl)carbonyl]-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino-[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 7.97 (s, 1H), 7.92 (d, J=8.7Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.69 (dd,J=8.7, 2.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.34 (d, J=2.1 Hz, 1H), 7.16(d, J=7.5 Hz, 1H), 6.99 (m, 2H), 3.63 (m, 1H), 3.45 (m, 1H), 2.83 (m,1H), 1.96 (m, 1H), 1.66 (m, 1H), 1.12 (d, J=6.6 Hz, 3H); MS (ESI) m/z580.0 (M+H⁺).

Example 305′-Bromo-3-methyl-10-{[4-(trifluoromethoxy)phenyl]sulfonyl}-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(24)

To a solution of compound 1 (20 mg, 0.05 mmol) in 0.5 mL of drydichloromethane is added triethylamine (14.0 μL, 0.101 mmol), followedby 4-(trifluoromethoxy)benzenesulphonyl chloride (20.6 μL, 0.121 mmol)and 4-dimethylaminopyridine (12.3 mg, 0.101 mmol). The solution isstirred for 16 h at room temperature under argon atmosphere. Thereaction mixture is concentrated to dryness. The crude mixture issubjected to flash chromatography column to afford compound 24 (9.1 mg,29%).

5′-Bromo-3-methyl-10-{[4-(trifluoromethoxy)phenyl]sulfonyl}-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.1 (s, 1H), 8.17 (d, J=9.0 Hz, 2H), 7.83(d, J=9.0 Hz, 1H), 7.73 (dd, J=2.1, 8.7 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H),7.47 (d, J=7.5 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H),7.05-6.93 (m, 2H), 3.48-3.38 (m, 1H), 3.11-3.02 (m, 1H), 2.83-2.74 (m,1H), 2.03-1.95 (m, 1H), 1.65-1.57 (m, 1H), 0.87 (d, J=6.6 Hz, 3H); MS(ESI) m/z 621.0 (M+H)⁺.

Example 315′-Bromo-10-[(4-methoxyphenyl)carbonyl]-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino-[3,4-b]indole-1,3′-indol]-2′(1′H)-one(25)

Compound 25 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Example 30.

5′-Bromo-10-[(4-methoxyphenyl)carbonyl]-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino-[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 7.80-7.75 (m, 2H), 7.72 (s,1H), 7.65 (dd, J=1.8, 8.7 Hz, 1H), 7.50 (d, J=6.9 Hz, 1H), 7.33 (d,J=1.8 Hz, 1H), 7.18-7.13 (m, 1H), 7.06-7.02 (m, 3H), 7.01-6.96 (m, 1H),3.84 (s, 3H), 3.72-3.65 (m, 1H), 3.24-3.14 (m, 1H), 2.88-2.79 (m, 1H),2.06-1.95 (m, 1H), 1.74-1.62 (m, 1H), 1.17 (d, J=6.6 Hz, 3H) ppm; MS(ESI) m/z 531.0 (M+H)⁺.

Example 32(1R,3S)-9-(3-aminopropyl)-5′-chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(26)

Compound 26 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Scheme F.

(1R,3S)-9-(3-aminopropyl)-5′-chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 11.81 (bs, 1H), 11.22 (bs, 1H), 10.95 (bs,1H), 7.93 (s, 1H), 7.67 (m, 1H), 7.61 (m 1H), 7.50 (m, 2H), 7.45 (m,3H), 4.41 (bs, 1H), 3.72 (m, 1H), 3.47 (m, 1H), 3.17 (m, 1H), 2.78 (m,3H), 1.16 (m, 3H); MS (ESI) m/z 395.2 (M+H)⁺.

Example 33N-{3-[(1R,3S)-5′-chloro-3-methyl-2′-oxo-1′,2′,3,4-tetrahydrospiro[β-carboline-1,3′-indol]-9(2H)-yl]propyl}acetamide(27)

Compound 27 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Scheme F.

N-{3-[(1R,3S)-5′-chloro-3-methyl-2′-oxo-1′,2′,3,4-tetrahydrospiro[β-carboline-1,3′-indol]-9(2H)-yl]propyl}acetamide:¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 8.13 (s, 1H), 7.67 (m, 1H),7.50 (d, J=8.0 Hz, 1H), 7.34 (m, 2H), 7.08 (m, 3H), 4.07 (m, 1H), 3.72(m, 1H), 3.47 (m, 1H), 3.17 (d, J=4.0 Hz, 1H), 2.78 (m, 3H), 1.78 (s,3H), 1.16 (d, J=8.0 Hz, 3H); MS (ESI) m/z 437.3 (M+H)⁺.

Example 34(3S,11a′S)-5-Chloro-3′,3′-dimethyl-1′,6′,11′,11a′-tetrahydrospiro[indole-3,5′-[1,3]oxazolo-[3′,4′:1,6]pyrido[3,4-b]indol]-2(1H)-one(28)

To a solution of compound 11 (15 mg, 0.04 mmol) in the mixture ofdichloromethane:2,2-dimethoxypropane (1 mL:0.5 mL) is added catalyticamount of pyridinium p-toluenesulfonate at room temperature. Theresulting mixture is stirred for 16 h at ambient temperature and thenconcentrated in vacuo. The residue is subjected to flash columnchromatography (silica gel, 10%-40% EtOAc in hexanes) to afford compound28 (7 mg, 42%) as white solid.

(3S,11a′S)-5-Chloro-3′,3′-dimethyl-1′,6′,11′,11a′-tetrahydrospiro[indole-3,5′-[1,3]oxazolo-[3′,4′:1,6]pyrido[3,4-b]indol]-2(1H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.49 (s, 1H), 10.45 (s, 1H), 7.46 (d,J=6.9 Hz, 1H), 7.33 (dd, J=8.1, 2.4 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H),7.07-6.59 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 4.03 (m, 1H), 3.43 (m, 2H),2.97 (d, J=6.3 Hz, 1H), 2.86 (dd, J=15.0, 3.9 Hz, 1H), 1.29 (s, 6H); MS(ESI) m/z 395.0 (M+H)⁺.

Example 353-Methyl-5′-phenyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(29)

A mixture of compound 1 (7 mg, 0.018 mmol), benzeneboronic acid (2.6 mg,0.021 mmol) and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol)in DMF (2 mL)/aqueous 2 N sodium bicarbonate solution (0.5 mL) isstirred for 20 minutes in a microwave reactor at 130° C. After beingcooled to room temperature, the reaction mixture is extracted with ethylacetate (3×10 mL). The combined organic phases are dried over sodiumsulfate and concentrated in vacuo. The residue is subjected to flashcolumn chromatography (silica gel, 30% EtOAc in hexanes) to affordcompound 29 (2.3 mg, 33%) as white solid.

3-Methyl-5′-phenyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.34 (s, 1H), 7.77 (m, 1H),7.59 (m, 2H), 7.42 (m, 4H), 7.29 (q, J=7.5 Hz, 1H), 7.16 (m, 1H), 6.99(d, J=7.8 Hz, 1H), 6.95 (m, 2H), 3.92 (m, 1H), 3.16 (m, 1H), 2.91 (m,1H), 2.11 (m, 1H), 1.67 (m, 1H), 1.06 (d, J=6.6 Hz, 3H); MS (ESI) m/z394.0 (M+H)⁺.

Example 363-Methyl-5′-[4-(trifluoromethyl)phenyl]-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(30)

Compound 30 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Example 34.

3-Methyl-5′-[4-(trifluoromethyl)phenyl]-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.48 (s, 1H), 9.96 (s, 1H), 7.84 (s, 1H),7.81 (s, 1H), 7.75-7.66 (m, 3H), 7.53 (d, J=1.8 Hz, 1H), 7.47-7.44 (m,1H), 7.18-7.14 (m, H), 7.03 (d, J=8.1 Hz, 1H), 6.99-6.91 (m, 2H),3.98-3.86 (m, 1H), 3.21-3.12 (m, 1H), 2.96-2.87 (m, 1H), 2.15-2.08 (m,1H), 1.73-1.61 (m, 1H), 1.06 (d, J=6.6 Hz, 3H); MS (ESI) m/z 462.0(M+H)⁺.

Example 373-Methyl-5′-(4-phenoxyphenyl)-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(31)

Compound 31 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Example 34.

3-Methyl-5′-(4-phenoxyphenyl)-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 9.94 (s, 1H), 7.61-7.56 (m,3H), 7.47-7.35 (m, 4H), 7.17-7.10 (m, 2H), 7.04-7.00 (m, 5H), 6.97-6.91(m, 2), 3.98-3.84 (m, 1H), 3.21-3.12 (m, 1H), 2.96-2.86 (m, 1H),2.14-2.07 (m, 1), 1.72-1.62 (m, 1H), 1.06 (d, J=6.6 Hz, 3H); MS (ESI)m/z 486.0 (M+H)⁺.

Example 385′-Chloro-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(32)

Compound 32 may be prepared according to Scheme D.

5′-Chloro-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.5 (s, 1H), 10.3 (s, 1H), 7.27 (dd,J=2.1, 7.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.94(d, J=2.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.66 (dd, J=2.4, 6.3 Hz, 1H),3.75 (s, 3H), 2.71 (q, J=12.3 Hz, 2H), 1.30 (s, 3H), 1.28 (s, 3H); MS(ESI) m/z 382.0 (M+H)⁺.

Example 395′-Chloro-3,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(33)

Compound 33 may be prepared using the same or analogous synthetictechniques and/or substituting with alternative reagents as describedabove in Example 37.

5′-Chloro-3,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.55 (s, 1H), 10.51 (s, 1H), 7.44 (d,J=7.51 Hz, 1H), 7.28 (dd, J=2.1, 8.4 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H),7.05-6.99 (m, 3H), 6.96-6.89 (m, 1H), 2.74 (q, J=12.3 Hz, 1H), 1.30 (s,3H), 1.29 (s, 3H); MS (ESI) m/z 352.0 (M+H)⁺.

Example 40 7-Chloroisatin

The title compound may be prepared according to Scheme E.

7-Chloroisatin: ¹H NMR (300 MHz, DMSO-d₆): δ 11.45 (s, 1H), 7.67 (dd,J=0.90, 7.95 Hz, 1H), 7.49 (dt, J=0.60, 7.2 Hz, 1H), 7.08 (dd, J=7.50,7.78 Hz, 1H); MS (ESI) m/z 180.0 (M+H)⁺.

Example 41 5-Methoxyisatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

5-Methoxyisatin: ¹H NMR (300 MHz, DMSO-d₆): δ 10.83 (s, 1H), 7.19 (dd,J=2.7, 8.6 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 3.75(s, 3H); MS (ESI) m/z 178.0 (M+H)⁺.

Example 42 6-Methoxyisatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

6-Methoxyisatin: ¹H NMR (300 MHz, DMSO-d₆): δ 10.96 (s, 1H), 7.49 (d,J=8.4 Hz, 1H), 6.59 (dd, J=2.4, 8.4, 1H), 6.40 (d, J=2.4 Hz, 1H), 3.88(s, 3H); MS (ESI) m/z 178.0 (M+H)⁺.

Example 43 7-(Trifluoromethyl)isatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

7-(trifluoromethyl)isatin: ¹H NMR (300 MHz, DMSO-d₆): δ 11.44 (s, 1H),7.85 (dd, J=8.1 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H);MS (ESI) m/z 214.0 (M+H)⁺.

Example 44 5-(tert-Butyl)isatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

5-(tert-butyl)isatin: ¹H NMR (300 MHz, DMSO-d₆): δ 10.95 (s, 1H), 7.65(dd, J=1.8, 8.3 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H),1.26 (s, 9H); MS (ESI) m/z 204.0 (M+H)⁺.

Example 45 6,7-Dichloroisatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

6,7-Dichloroisatin: ¹H NMR (300 MHz, DMSO-d₆): δ 11.63 (s, 1H), 7.51(dd, J=0.90, 7.95 Hz, 1H), 7.33 (d, J=7.80 Hz, 1H); MS (ESI) m/z 216.0(M+H)⁺.

Example 46 4,7-Dichloroisatin

The title compound may be prepared according to Scheme E using the sameor analogous synthetic techniques and/or substituting with alternativereagents.

4,7-Dichloroisatin: ¹H NMR (300 MHz, DMSO-d₆): δ 11.60 (s, 1H), 7.65 (d,J=9 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H); MS (ESI) m/z 214.0 (M+H)⁺.

Example 47(1R,3S)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one.(34)

Compound 34 may be prepared according to Scheme F.

(1R,3S)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 10.42 (s, 1H), 7.43 (d,J=7.2 Hz, 1H), 7.31 (dd, J=2.1, 8.4 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),7.05-7.02 (m, 2H), 7.00-6.96 (m, 1H), 6.92 (d, J=8.1 Hz, 1H), 3.98-3.86(m, 1H), 2.79 (dd, J=, 14.9, 3.3 Hz, 1H), 2.41 (dd, J=4.5, 2.5 Hz, 1H),1.18 (d, J=6.0 Hz, 3H); MS (ESI) m/z 338.0 (M+H)⁺.

Example 48(1S,3R)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(35)

Compound 35 may be prepared according to Scheme F using the same oranalogous synthetic techniques and/or substituting with alternativereagents.

(1S,3R)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 10.42 (s, 1H), 7.43 (d,J=7.5 Hz, 1H), 7.31 (dd, J=2.1, 8.4 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),7.05-7.02 (m, 2H), 7.00-6.96 (m, 1H), 6.92 (d, J=8.1 Hz, 1H), 3.98-3.86(m, 1H), 2.78 (dd, J=3.6, 14.9 Hz, 1H), 2.41 (dd, J=4.5, 25.5 Hz, 1H),1.18 (d, J=6.3 Hz, 3H); MS (ESI) m/z 338.0 (M+H)⁺.

Chiral compounds such as 36 and 37 can be prepared according to Scheme Gor H using the same or analogous synthetic techniques and/orsubstituting with alternative reagents.

Example 49(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(36)

35: ¹H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.51 (s, 1H), 7.43 (d,J=10.0 Hz, 1H), 7.33 (dd, J=8.4, 2.2 Hz, 1H), 7.27 (d, J=6.5 Hz, 1H),7.05 (d, J=2.3, 1H), 6.93 (d, J=8.5 Hz, 1H), 3.91 (m, 1H), 3.13 (bd,J=6.2 Hz, 1H), 2.74 (dd, J=15.0, 3.0 Hz, 1H), 2.35 (dd, J=15.0, 10.3,1H), 1.15 (d, J=6.0, 3H); MS (ESI) m/z 392.0 (M+2H)⁺; [α]²⁵ _(D)=+255.4°

Example 50(1S,3R)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(37)

(1S,3R)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 7.54 (s, 1H), 7.24 (d, J=9.7 Hz,1H), 7.21 (dd, J=8.6, 2.0 Hz, 1H), 7.14 (d, J=6.0 Hz, 1H), 7.11 (d,J=1.8, 1H), 6.77 (d, J=8.3 Hz, 1H), 4.14 (m, 1H), 2.89 (dd, J=15.4, 3.7Hz, 1H), 2.49 (dd, J=15.3, 10.5, 1H), 1.68 (bs, 1H), 1.29 (d, J=6.4 Hz,3H); MS (ESI) m/z 392.0 (M+2H)⁺; [α]²⁵ _(D)−223.3°

Example 513-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(38)

3-Methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one: ¹HNMR (300 MHz, DMSO-d6): δ 10.34 (s, 1H), 10.30 (s, 1H), 7.39-7.45 (m,1H), 7.26 (td, J=7.6, 1.5 Hz, 1H), 7.12-7.18 (m, 1H), 6.85-7.08 (m, 5H),3.89-4.02 (m, 1H), 2.79 (dd, J=14.9, 3.8 Hz, 1H), 2.41 (dd, J=14.910.6Hz, 1H), 1.18 (d, J=6.5 Hz, 3H); MS (ESI) m/z 304.0 (M+H)⁺.

Example 526′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one(39)

6′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.46 (s, 1H), 10.39 (s, 1H), 7.42 (d,J=7.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.87-7.07 (m, 5H), 3.86-4.04 (m,1H), 3.03 (d, J=5.3 Hz, 1H), 2.78 (dd, J=14.9, 3.8 Hz, 1H), 2.40 (dd,J=14.9, 10.6 Hz, 1H), 1.17 (d, 3H); MS (ESI) m/z 338.0 (M+H)⁺.

Example 535′-tert-Butyl-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one(40)

5′-tert-Butyl-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one:¹H NMR (300 MHz, MeOD-d₄): δ 8.25 (s, 1H), 7.33-7.58 (m, 3H), 6.94-7.26(m, 4H), 4.42-4.56 (m, 1H), 3.10 (dd, J=15.0, 6.0 Hz, 1H), 2.77 (dd,J=15.8, 10.8 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z360.0 (M+H)⁺.

Example 546′,7′-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one(41)

6′,7′-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.92 (s, 1H), 10.49 (s, 1H), 7.43 (d,J=7.0 Hz, 1H), 7.10-7.24 (m, 2H), 6.92-7.08 (m, 3H), 3.84-4.13 (m, 1H),3.24 (d, J=4.7 Hz, 1H), 2.79 (dd, J=14.8, 3.7 Hz, 1H), 2.40 (dd, J=14.9,10.6 Hz, 1H), 1.18 (d, J=6.15 Hz, 3H); MS (ESI) m/z 372.0 (M+H)⁺.

Example 553-Methyl-7′-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(42)

3-Methyl-7′-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.74 (s, 1H), 10.48 (s, 1H), 7.54 (d,J=7.9 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H),6.89-7.19, (m, 4H), 3.87-4.10 (m, 1H), 3.17 (d, J=5.3 Hz, 1H), 2.81 (dd,J=15.1, 3.7 Hz, 1H), 2.43 (dd, J=14.9, 10.6 Hz, 1H), 1.18 (d, J=6.5 Hz,3H); MS (ESI) m/z 372.0 (M+H)⁺.

Example 567′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(43)

7′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, MeOD-d₄): δ 7.48-7.58 (m, 2H), 7.03-7.32 (m, 5H),4.68-4.84 (m, 1H), 3.25 (d, J=4.4 Hz, 1H), 2.92 (dd, J=16.3, 11.0 Hz,1H), 1.55 (d, J=6.7 Hz, 3H); MS (ESI) m/z 338.0 (M+H)⁺.

Example 575′-Chloro-2,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(44)

5′-Chloro-2,3-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹HNMR (300 MHz, DMSO-d₆): δ 10.68 (s, 1H), 10.32 (s, 1H), 7.43 (d, J=7.0Hz, 1H), 7.35 (dd, J=8.4, 2.2 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.91-7.07(m, 4H), 3.74-3.89 (m, 1H), 2.85 (dd, J=15.2, 3.8 Hz, 1H), 2.51-2.62 (m,1H), 2.09 (s, 3H), 1.24 (d, 3H); MS (ESI) m/z 352.0 (M+H)⁺.

Example 585′-Chloro-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(45)

5′-Chloro-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.56 (s, 1H), 10.10 (s, 1H), 7.46 (d,J=7.0 Hz, 1H), 7.32 (dd, J=8.4, 2.2 Hz, 1H), 7.1-7.16 (m, 2H), 6.95 (t,J=7.8 Hz, 1H), 6.91-7.03 (m, 2H), 3.47 (ddd, J=14.2, 7.3, 5.1 Hz, 2H),2.91-3.17 (m, 3H), 1.88-2.06 (m, 2H); MS (ESI) m/z 338.0 (M+H)⁺.

Example 59(1R,3S)-5′-Bromo-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(46)

(1R,3S)-5′-Bromo-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.46 (s, 1H), 10.42 (s, 1H), 7.44 (dd,J=8.2, 2.1 Hz, 2H), 7.11-7.21 (m, 2H), 6.92-7.07 (m, 2H), 6.88 (d, J=8.5Hz, 1H), 3.84-3.98 (m, 1H), 2.78 (dd, J=15.1, 3.7 Hz, 1H), 2.41 (dd,J=15.1, 10.4 Hz, 1H), 1.18 (d, J=6.5 Hz, 3H); MS (ESI) m/z 383.0 (M+H)⁺;[α]²⁵ _(D)+244.9°.

To a solution of 5-chloroindole-3-carboxaldehyde (2.14 g; 11.7 mmol) intoluene (22 mL) was added nitroethane (25.2 mL) and ammonium acetate(0.5 g, 6.5 mmol). The reaction mixture was stirred at reflux (130° C.)for 5 hours. Afterward, additional ammonium acetate (0.43 g, 5.9 mmol)was added and the reflux was continued. After an one hour, an additionalamount of ammonium acetate (0.44 g, 5.9 mmol) was added. The reactionmixture was refluxed for another hour and was then left to stand at roomtemperature overnight. The precipitate formed was collected byfiltration, washed with toluene and placed under high vacuum to affordthe nitro intermediate as bright yellow powder (2.69 g, 97.1%). ¹HNMR(300 MHz, DMSO-d₆): δ 8.42 (s, 1H), 8.06 (s, 1H), 7.95 (d, J=2.05 Hz,1H), 7.52 (d, J=9.1 Hz, 1H), 7.24 (dd, J=8.5, 2.1 Hz, 1H), 2.48 (s, 3H),1.86 (s, 2H); MS (ESI) m/z 236.0 (M+H)⁺.

To a suspension of lithium aluminum hydride (2.62 g, 68.2 mmol) intetrahydrofuran (70 mL) was added the nitro intermediate (2.69 g, 11.37mmol) in small portions. The resulting reaction mixture was refluxed at90° C. for 6 hours. Afterward, the reaction mixture was cooled to roomtemperature and placed in an ice bath. It was then quenched by adding awater-THF mixture (6:4, 70 mL) slowly, followed by aqueous sodiumhydroxide (4 M, 70 mL). The resultant suspension was allowed to stirovernight and was then filtered through celite. The filtrate obtainedwas concentrated in vacuo, diluted with water and extracted with ethylacetate. The extracts was washed with water and brine, dried by sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was placed under high vacuum to afford2-(5-chloro-1H-indol-3-yl)-1-methyl-ethylamine as a brown oil (2.25 g,94.9%). ¹HNMR (300 MHz, DMSO-d₆): δ 11.01 (bs, 1H), 7.55 (d, J=2.05 Hz,1H), 7.34 (d, J=9.08 Hz, 1H), 7.20 (d, J=1.76 Hz, 1H), 7.04 (dd, J=8.5,2.1 Hz, 1H), 2.96-3.10 (m, 1H), 2.60 (d, J=6.5 Hz, 2H), 0.97 (d, J=6.5Hz, 3H); MS (ESI) m/z 208.0 (M+H)⁺.

Example 60(1R,3S)-5′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(47)

(1R,3S)-5′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.96 (s, 1H), 7.46 (dd,J=6.6 Hz, J=1.8 Hz, 1H), 7.32 (dd, J=8.1 Hz, J=2.4 Hz, 1H), 7.17 (m,2H), 6.96 (m, 3H), 3.90 (m, 1H), 3.12 (m, 1H), 2.88 (m, 1H), 2.78 (d,J=5.7 Hz, 1H), 2.08 (m, 1H), 1.64 (m, 1H), 1.05 (d, J=6.3 Hz, 3H); MS(ESI) m/z 352.0 (M+H)⁺; [α]²⁵ _(D)+238.8°.

Example 61(1S,3R)-5′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one(48)

(1S,3R)-5′-Chloro-3-methyl-3,4,5,10-tetrahydro-2H-spiro[azepino[3,4-b]indole-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.96 (s, 1H), 7.46 (dd,J=6.6 Hz, J=1.5 Hz, 1H), 7.33 (dd, J=8.1 Hz, J=2.4 Hz, 1H), 7.17 (m,2H), 6.96 (m, 3H), 3.90 (m, 1H), 3.12 (m, 1H), 2.88 (m, 1H), 2.78 (d,J=5.4 Hz, 1H), 2.08 (m, 1H), 1.64 (m, 1H), 1.05 (d, J=6.3 Hz, 3H); MS(ESI) m/z 352.0 (M+H)⁺; [α]²⁵ _(D)−237.6°.

Example 62(1R,3S)-5′,6-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one

(49)

(1R,3S)-5′,6-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.66 (s, 1H), 10.50 (s, 1H), 7.47 (d,J=2.1 Hz, 1H), 7.32 (dd, J=8.1 Hz, J=2.1 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 7.04 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 3.92 (m, 1H), 3.10 (d, J=5.7Hz, 1H), 2.78 (m, 1H), 2.39 (m, 1H), 1.17 (d, J=6.3 Hz, 3H); MS (ESI)m/z 373.0 (M+H)⁺; [α]²⁵ _(D)+141.2°.

Example 63(1S,3R)-5′,6-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(50)

(1S,3R)-5′,6-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.66 (s, 1H), 10.49 (s, 1H), 7.48 (d,J=2.1 Hz, 1H), 7.32 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 7.03 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 3.92 (m, 1H), 3.11 (m, 1H),2.78 (m, 1H), 2.39 (m, 1H), 1.17 (d, J=6.3 Hz, 3H); MS (ESI) m/z 373.0(M+H)⁺; [α]²⁵ _(D)−171.20°.

Example 64(1R,3S)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(51)

(1R,3S)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 10.48 (s, 1H), 7.32 (dd, 1H,J=8.3, 2.2 Hz), 7.20 (dd, 1H, J=9.8, 2.3 Hz), 7.16 (dd, 1H, J=8.8, 4.6Hz), 7.06 (d, 1H, J=1.5 Hz), 6.93 (d, 1H, J=6.0 Hz), 6.87 (dt, 1H,J=6.9, 1.8 Hz), 3.95 (m, 1H), 3.35 (bs, 1H), 2.77 (dd, 1H, J=15.0, 3.7Hz), 2.40 (dd, 1H, J=15.0, 10.6 Hz), 1.18 (d, 3H, J=6.4 Hz); HRMS:355.0890 (M+), calculated for C₁₉H₁₅ClFN₃O; [α]²⁵ _(D)+211.6°

Example 65(1S,3R)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(52)

(1S,3R)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d6): δ 10.55 (s, 1H), 10.51 (s, 1H), 7.32 (dd,J=8.4 Hz, J=2.4 Hz, 1H), 7.20 (dd, J=10.1 Hz, J=2.4 Hz, 1H), 7.14 (dd,J=8.8 Hz, J=4.5 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H),6.86 (td, J=9.3 Hz, J=2.4 Hz, 1H), 3.93 (m, 1H), 2.76 (dd, J=15.0 Hz,J=3.6 Hz, 1H), 2.39 (dd, J=15.2 Hz, J=10.5 Hz, 1H), 1.17 (d, J=6.3 Hz,3H); MS (ESI) m/z 357.0 (M+H)⁺; [α]_(D)−208.8°.

Example 665′-Chloro-3-propyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(53)

5′-Chloro-3-propyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 10.40 (s, 1H), 7.44 (d,J=7.5 Hz, 1H), 7.31 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.16 (d, J=7.5 Hz,1H), 6.98 (m, 4H), 3.79 (m, 1H), 2.80 (dd, J=15.0 Hz, J=3.6 Hz, 1H),2.40 (m, 1H), 1.46 (m, 4H), 0.91 (t, J=6.9 Hz, 1H); MS (ESI) m/z 366.0(M+H)⁺.

The following trifluoromethyl compounds can be prepared according to thefollowing scheme.

Example 67 3-Bromo-1,1,1-trifluoro-propan-2-one oxime

To a solution of 2.5 g of 1-bromo-3,3,3-trifluoropropan-2-one in 15 mLof chloroform (passed through a pad of basic alumina) was added asolution of hydroxylamine hydrochloride in 2.5 mL of water and themixture heated to reflux. After 25 hours, the reaction mixture wascooled and 15 mL of H₂O was added. The layers were separated and theaqueous layer was washed with 3×15 mL dichloromethane. The combinedorganic extracts were dried over magnesium sulfate, filtered andconcentrated in vacuo. Note: As the product is a volatile liquid,excessive application of the vacuum to remove the co-solvent reduced theyield of the product. it's the product was used without furtherpurification.

Example 68 1,1,1-Trifluoro-3-(5-fluoro-1H-inol-3-yl)-propan-2-one oxime

To a solution of 362.5 mg of 3-bromo-1,1,1-trifluoro-propan-2-one oximein 20 mL of MTBE was added 5-fluoroindole and sodium carbonate and themixture stirred at room temperature. After 2 hours, the reaction wasfiltered through celite and concentrated in vacuo. The residue waspurified on silica gel (hexane:ethyl acetate from 0% to 30% ethylacetate) to provide the desired product. ¹H NMR (300 MHz, DMSO-d₆):111.00 (bs, 1H) 7.32 (m, 3H) 6.91 (td, J=9.2, 2.4 Hz, 1H) 3.48 (m, 1H)3.02 (dd, J=14.5, 3.2 Hz, 1H) 2.70 (dd, J=14.5, 9.6 Hz, 1H), 1.84 (bs,2H); MS (ESI) m/z 247.0 (M+H)⁺.

Example 69 2,2,2-Trifluoro-1-(5-fluoro-1H-indol-3-ylmethyl)ethylamine

To a solution of 280 mg of1,1,1-trifluoro-3-(5-fluoro-1H-inol-3-yl)-propan-2-one oxime in diethylether was added 5 mL of 2M lithium aluminium hydride in THF dropwise at0° C. The reaction was stirred at 0° C., then warmed to roomtemperature. After, 21 hours, the reaction was carefully quenched withwater until no effervescence was observed. The mixture was then driedover magnesium sulfate, filtered through celite and concentrated todryness. The residue was purified on silica gel (100% hexane to 65-70%hexane in ethyl acetate).

Example 70(1S,3R)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(54)

(1S,3R)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ11.01 (s, 1H), 10.78 (s, 1H), 7.54 (m, 2H),7.35 (dd, J=8.7, 2.1 Hz, 1H), 7.120 (m, 1H), 7.08 (td, J=7.5, 1.5 Hz,1H), 7.01 (m, 2H), 4.36 (m, 1H), 3.13 (dd, J=15.0, J=3.9 Hz, 1H), 2.85(dd, J=15.0, J=11.1 Hz, 1H), 2.54 (d, J=11.7 Hz, 1H); MS (ESI) m/z 392.0(M+H)⁺.

Example 71(1R,3R)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(55)

(1R,3R)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.70 (s, 1H), 10.62 (s, 1H), 7.53 (d,J=7.5 Hz, 1H), 7.38 (dd, J=8.4, 2.4 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H),7.21 (m, 1H), 7.08 (td, J=7.2, 1.2 Hz, 1H), 7.00 (m, 2H), 4.62 (m, 1H),3.75 (d, J=9.0 Hz, 1H), 2.98 (m, 2H); MS (ESI) m/z 392.0 (M+H)⁺; [α]²⁵_(D)+274.5°.

Example 72(1R,3S)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(56)

(1R,3S)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 11.01 (s, 1H), 10.78 (s, 1H), 7.54 (m, 2H),7.35 (dd, J=8.6 Hz, J=2.3 Hz, 1H), 7.20 (m, 1H), 7.082 (td, J=7.6 Hz,J=1.3 Hz, 1H), 7.01 (m, 2H), 4.36 (m, 1H), 3.13 (dd, J=15.0 Hz, J=3.9Hz, 1H), 2.85 (dd, J=15.2 Hz, J=11.0 Hz, 1H), 2.54 (m, 1H); MS (ESI) m/z392.0 (M+H)⁺.

Example 73(1S,3S)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(57)

(1S,3S)-5′-Chloro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.69 (s, 1H) 10.62 (s, 1H), 7.53 (d, J=7.8Hz, 1H), 7.38 (dd, J=8.3, 2.3 Hz, 1H) 7.29 (d, J=2.4 Hz, 1H), 7.20 (d,J=7.1 Hz, 1H), 7.08 (td, J=8.0 Hz, 1.0 Hz, 1H) 7.00 (m, 2H), 4.61 (m,1H), 3.74 (d, J=9.1 Hz, 1H), 2.97 (m, 2H); MS (ESI) m/z 392.0 (M+H)⁺;[α]²⁵ _(D)−295.4°.

Example 745′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(58)

5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.53 (s, 1H), 10.47 (s, 1H), 7.32 (dd,J=1.8, 8.4 Hz, 1H), 7.19 (dd, J=2.4, 9.9 Hz, 1H), 7.13 (dd, J=4.5, 8.9Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.85 (td,J=2.7, 8.9 Hz, 1H), 3.98-3.83 (m, 1H), 2.76 (dd, J=3.9, 14.9 Hz, 1H),2.38 (dd, J=10.2, 15.2 Hz, 1H), 1.17 (d, J=5.1 Hz, 3H); MS (ESI) m/z356.0 (M+H)⁺.

Example 755,5′-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(59)

5,5′-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.79 (s, 1H), 10.50 (s, 1H), 7.32 (dd,J=2.4, 8.3 Hz, 1H), 7.12 (dd, J=2.7, 6.0 Hz, 1H), 7.04 (d, J=2.1 Hz,1H), 6.98 (d, J=3.6 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=8.4 Hz, 1H),3.98-3.86 (m, 1H), 3.19 (dd, J=3.9, 15.3 Hz, 1H), 2.61 (dd, J=10.5, 15.5Hz, 1H), 1.17 (d, J=6.6 Hz, 3H); MS (ESI) m/z 373.0 (M+H)⁺.

Example 765′,7-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(60)

5′,7-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.79 (s, 1H), 10.50 (s, 1H), 7.45 (d,J=8.1 Hz, 1H), 7.32 (dd, J=2.4, 8.1 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H),7.04 (d, J=2.1 Hz, 1H), 6.98 (dd, J=1.8, 8.4 Hz 1H), 6.93 (d, J=8.4 Hz,1H), 3.98-3.84 (m, 1H), 2.78 (dd, J=3.9, 15.2 Hz, 1H), 2.39 (dd, J=10.8,15.0 Hz, 1H), 1.17 (d, J=6.3 Hz, 3H); MS (ESI) m/z 373.0 (M+H)⁺.

Example 775′,8-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(61)

5′,8-Dichloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.93 (s, 1H), 10.42 (s, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.32 (dd, J=2.4, 8.4 Hz, 1H), 7.11 (dd, J=0.9, 7.5 Hz,1H), 6.99 (s, 1H), 6.99 (dd, J=6.3, 8.7 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),3.90-3.76 (m, 1H), 2.80 (dd, J=3.9, 15.0 Hz, 1H), 2.43 (dd, J=10.5, 15.0Hz, 1H), 1.16 (d, J=6.6 Hz, 3H); MS (ESI) m/z 373.0 (M+H)⁺.

Example 785′-Chloro-3,6-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(62)

5′-Chloro-3,6-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 10.26 (s, 1H), 7.30 (dd,J=8.4, 2.4 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.01 (d, J=2.4Hz, 1H), 6.91 (d, J=8.4 Hz 1H), 6.84 (dd, J=8.3, 1.5 Hz, 1H), 3.98-3.85(m, 1H), 2.74 (dd, J=14.9, 3.6 Hz, 1H), 2.38 (dd, J=15.2, 10.5 Hz, 1H),2.36 (s, 3H), 1.17 (d, J=6.6 Hz, 3H); MS (ESI) m/z 352.0 (M+H)⁺.

Example 796-Bromo-5′-chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(63)

6-Bromo-5′-chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.67 (s, 1H), 10.49 (s, 1H), 7.61 (s, 1H),7.32 (dd, J=8.3, 2.1 Hz, 1H), 7.13 (s, 1H), 7.12 (s, 1H), 7.03 (d, J=2.1Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 3.98-3.84 (m, 1H), 2.78 (dd, J=15.2,3.6 Hz, 1H), 2.38 (dd, J=15.3, 10.5 Hz, 1H), 1.17 (d, J=6.3 Hz, 3H); MS(ESI) m/z 417.0 (M+H)⁺.

Example 805′-Chloro-6-methoxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(64)

5′-Chloro-6-methoxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 10.23 (s, 1H), 7.30 (dd,J=8.3, 2.4 Hz, 1H), 7.04 (d, J=11.4 Hz, 1H), 7.03 (s, 1H), 6.93 (d,J=2.4 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.66 (dd, J=2.4, 8.6 Hz, 1H),3.98-3.86 (m, 1H), 3.75 (s, 3H), 2.75 (dd, J=14.9, 3.6 Hz, 1H), 2.38(dd, J=15.2, 10.2, Hz 1H), 1.17 (d, J=6.6 Hz, 3H); MS (ESI) m/z 368.0(M+H)⁺.

Example 815′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(65)

Compound 65 can be prepared according to the following procedure.

To a solution of 64 (157 mg, 0.428 mmol) in 12 mL DCM was added borontrichloride (1M in dichloromethane) (2.14 mL, 2.14 mmol) cautiously inan ice bath. Additional aliquots of boron trichloride were added afterthe three, six and eight hours. After the last addition, the reactionwas left to stir at room temperature for 18 hours. Upon completion, thereaction was quenched with sat NaHCO₃. The mixture was washed withdichloromethane, followed by EtOAc. The organic layers were combinedthen dried with sodium sulfate, filtered and concentrated in vacuo. Theproduct was isolated by flash column chromatography with the gradient1-3% MeOH in dichloromethane to provide 65 (100 mg, 66).

5′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 10.06 (s, 1H), 8.58 (s, 1H),7.30 (dd, J=8.3, 2.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.94 (d, J=9.0 Hz,1H), 6.90 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.53 (dd, J=8.7,2.4 Hz, 1H), 3.98-3.84 (m, 1H), 2.66 (dd, J=14.9, 3.6 Hz, 1H), 2.33 (dd,J=15.0, 10.5 Hz, 1H), 1.16 (d, J=6.6 Hz, 3H); MS (ESI) m/z 354 (M+H).

Example 82(1R,3S)-5′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(66)

(1R,3S)-5′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.44 (s, 1H), 10.08 (s, 1H), 8.61 (s, 1H),7.32 (d, J=8.0 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.92 (d,J=8.5 Hz, 1H), 6.75 (s, 1H), 6.56 (d, J=8.5 Hz, 1H), 3.93 (m, 1H), 2.69(d, J=14.0 Hz, 1H), 2.35 (m, 1H), 1.18 (d, J=5.3 Hz, 3H); MS (ESI) m/z353.9 (M+H)⁺; [α]²⁵ _(D): +204.0°.

Example 83(1S,3R)-5′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(67)

(1S,3R)-5′-Chloro-6-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.42 (s, 1H), 10.07 (s, 1H), 8.59 (s, 1H),7.31 (d, J=7.5 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.91 (d,J=8.0 Hz, 1H), 6.74 (s, 1H), 6.55 (d, J=8.5 Hz, 1H), 3.92 (m, 1H), 2.68(d, J=14.3 Hz, 1H), 2.35 (m, 1H), 1.17 (d, J=5.2 Hz, 3H); MS (ESI) m/z353.9 (M+H)⁺; [α]²⁵ _(D): −197.6°.

Example 845′-Chloro-7-methoxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(68)

5′-Chloro-7-methoxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 8.51 (bs, 1H), 7.46 (bs, 1H), 7.40 (d, J=8.6Hz, 1H), 7.14 (dd, J=8.3, 2.1 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 6.77 (dd,J=8.7, 2.2 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 4.16(m, 1H), 3.75 (s, 3H), 2.93 (dd, J=15.5, 3.9 Hz, 1H), 2.52 (dd, J=15.4,10.5 Hz, 1H), 1.28 (d, J=6.4 Hz, 3H); MS (ESI) m/z 368.0 (M)⁺.

Example 855′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(69)

5′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.41 (s, 1H), 10.00 (s, 1H), 8.80 (s, 1H),7.31 (bd, J=7.0 Hz, 1H), 7.19 (bd, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91(bd, J=8.5 Hz, 1H), 6.56 (s, 1H), 6.49 (bd, J=8.0 Hz, 1H), 3.90 (bs,1H), 2.96 (bs, 1H), 2.70 (bd, J=14.2 Hz, 1H), 2.36 (bt, J=9.8 Hz, 1H),1.17 (bs, 3H); MS (ESI) m/z 352.1 (M)⁺.

Example 86(1R,3S)-5′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(70)

(1R,3S)-5′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.41 (s, 1H), 10.00 (s, 1H), 8.80 (s, 1H),7.31 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91 (d,J=8.0 Hz, 1H), 6.56 (s, 1H), 6.49 (d, J=8.5 Hz, 1H), 3.90 (bs, 1H), 2.96(bs, 1H), 2.70 (bd, J=14.4 Hz, 1H), 2.36 (bt, J=12.2 Hz, 1H), 1.18 (d,J=6.4 Hz, 3H); MS (ESI) m/z 352.0 (M)⁺; [α]²⁵ _(D): 203.2°.

Example 87(1S,3R)-5′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(71)

(1S,3R)-5′-Chloro-7-hydroxy-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.41 (s, 1H), 10.00 (s, 1H), 8.81 (s, 1H),7.31 (bd, J=6.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.03 (bs, 1H), 6.91(bd, J=7.0 Hz, 1H), 6.56 (s, 1H), 6.49 (d, J=8.0 Hz, 1H), 3.90 (bs, 1H),2.96 (bs, 1H), 2.70 (bd, J=13.2 Hz, 1H), 2.36 (bs, 1H), 1.18 (d, J=6.6Hz, 3H); MS (ESI) m/z 352.1 (M)⁺; [α]²⁵ _(D): −228.1°.

Example 885′-Chloro-3-methyl-6-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(72)

5′-Chloro-3-methyl-6-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.96 (s, 1H), 10.52 (s, 1H), 7.82 (s, 1H),7.38-7.29 (m, 3H), 7.04 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H),4.01-3.83 (m, 1H), 2.88 (dd, J=15.0, 3.3 Hz, 1H), 2.44 (dd, J=15.3, 10.5Hz, 1H), 1.18 (d, J=6.3 Hz, 3H); MS (ESI) m/z 406.0 (M+H)⁺.

Example 895′-Chloro-3-methyl-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-6-carbonitrile(73)

5′-Chloro-3-methyl-2′-oxo-1′,2,2′,3,4,9-hexahydrospiro[β-carboline-1,3′-indole]-6-carbonitrile:Compound 63 (30 mg, 0.072 mmol), CuCN (9.67 mg, 0.108 mmol) inN-methylpyrrolidone (0.12 mL) was refluxed for 16 hr. The solvent wasremoved under reduced pressure overnight and the black residue wasstirred for 30 minutes with 30% aq. ammonia (0.2 mL), followed byaddition of chloroform. An insoluble material was filtered off andwashed 5 times with boiling chloroform. The organic phases werecombined, washed with water and dried with sodium sulfate. The productwas isolated using flash column chromatography with 10%-35% EtOAc inhexane (3.0 mg, 11.5%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.11 (s, 1H),10.54 (s, 1H), 7.99 (s, 1H), 7.92-7.83 (m, 3H), 7.05 (d, J=2.1 Hz, 1H),6.94 (d, J=8.4 Hz, 1H), 3.98-3.85 (m, 1H), 2.85 (dd, J=15.5, 3.6 Hz,1H), 2.42 (dd, J=15.3, 10.5 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H); MS (ESI)m/z 363.0 (M+H)⁺.

Example 90(1R,3S)-5′-Chloro-3,9-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(74)

The following scheme was used to prepare Compound 74.

The acetonide starting material was a side product obtained from the Cbzprotection of D-tryptophanol. D-Tryptophanol (500 mg, 2.27 mmol) wasdissolved in a mixture of 11.3 mL water and 11.3 mL acetone. Sodiumcarbonate (482 mg, 3.92 mmol) was added to the stirred, ice-cooledmixture followed by dropwise addition of benzyl chloroformate (0.374 mL,2.29 mmol). The cooling bath was removed and the reaction was stirred atroom temperature for 1.5 hours. The reaction mixture was acidified to pH2 with concentrated HCl and diluted with of water. The aqueous mixturewas extracted with EtOAc. The combined organics were then dried withmagnesium sulfate, filtered and concentrated in vacuo. The side productwas isolated using flash column chromatography with the gradient 0-20%EtOAc in hexane followed by 20% EtOAc in hexane.

To a stirring solution of the acetonide side product (1.5 g, 4.12 mmol)in 20.6 mL dry THF was added sodium hydride (197.6 mg, 4.94 mmol)followed by methyl iodide (0.513 mL, 8.23 mmol). The reaction mixturewas stirred at room temperature for 16 hours. Upon removal of THF, theresidue was taken up in EtOAc and this organic layer was washed withsaturated sodium chloride. The aqueous layer was back-washed with anadditional 20 mL EtOAc. The combined organics were dried with sodiumsulfate, filtered and concentrated in vacuo. The product was isolatedusing flash column chromatography with 5-10% EtOAc in hexane followed by10-30% EtOAc in hexane. (728.5 mg, 47%)

The N-methylated intermediate (700 mg, 1.85 mmol) was dissolved in 6.2mL dry dichloromethane. 4N HCl in 1,4-dioxane (4.63 mL, 18.5 mmol) wasadded to the mixture. The reaction was stirred at room temperature for16 hours. The reaction was concentrated in vacuo and the residue wastaken up in dichloromethane. The organic layer was washed with saturatedsodium chloride. The organic layer was dried with sodium sulfate,filtered and concentrated in vacuo. The product was isolated using flashcolumn chromatography with 20% EtOAc in hexane, followed by gradient20-50% EtOAc in hexane (305.7 mg, 49%)

A solution of the acetonide deprotected intermediate (300 mg, 0.888mmol) and triethylamine (0.24 mL, 1.73 mmol) in anhydrousdichloromethane (2.5 mL) was cooled to 0° C. p-Toluenesulfonyl chloride(179 mg, 0.941 mmol) was added and the solution was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated invacuo. The product was isolated using flash column chromatography with10-30% EtOAc in hexane, to provide ˜400 mg of product.

The tosylate (400 mg, 0.813 mmol) was dissolved in 24.2 mL absoluteethanol and 48.8 mg palladium (II) hydroxide catalyst was added. Thereaction mixture was stirred at room temperature for 2 hours. Thecatalyst was filtered through celite and the filtrate was concentratedin vacuo. 1M NaOH was added to the residue and the aqueous layer wasextracted twice with EtOAc. The combined organics were dried with sodiumsulfate, filtered and concentrated in vacuo. The residue was thendissolved in 1M NaOH and the aqueous layer was extracted twice withEtOAc. The combined organic layers were dried with sodium sulfate,filtered and concentrated in vacuo. (132.5 mg, 87%)

(1R,3S)-5′-Chloro-3,9-dimethyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:The methylated tryptamine (30 mg, 0.160 mmol) and 5-chloroisatin (28.9mg, 0.160 mmol) was dissolved in 0.56 mL absolute ethanol, followed bythe addition of p-TsOH (3.04 mg, 0.016 mmol). The reaction mixture wasstirred for 16 hours at 110° C. The reaction mixture was concentrated invacuo. The product was isolated using flash column chromatography with10-30% EtOAc in hexane, followed by isocratic 30% EtOAc in hexanes (50.3mg, 89%). ¹H NMR (300 MHz, DMSO-d₆): δ 10.68 (s, 1H), 7.49 (d, J=7.2 Hz,1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.13 (td,J=7.2, 1.2 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 7.03 (td, J=7.7, 1.2 Hz,1H), 6.96 (d, J=8.1 Hz, 1H), 3.82-3.64 (m, 1H), 3.02 (s, 3H), 2.82 (dd,J=15.0, 3.6 Hz, 1H), 2.47 (dd, J=15.0, 10.5 Hz, 1H), 1.17 (d, J=6.6 Hz,3H); MS (ESI) m/z 352.0 (M+H)⁺.

The following compounds may be prepared using the same or analogoussynthetic techniques and/or substituting with alternative reagents asdescribed in the previous examples.

Example 91(1R,3R)-5′-Chloro-6,7-difluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(75)

(1R,3R)-5′-Chloro-6,7-difluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.42 (s, 1H), 7.33 (dd, J=8.4,2.1 Hz, 1H), 7.31-7.28 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 6.99 (dd,J=10.3, 6.5 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.77-4.76 (m, 1H), 3.10(dd, J=15.3, 4.4 Hz, 1H), 2.97 (dd, J=15.3, 11.0 Hz, 1H), 2.14 (d, J=3.8Hz, 1H); MS (ESI) m/z 427.9 (M+H)⁺; [α]²⁵ _(D): +205.3°.

Example 92(1S,3S)-5′-Chloro-6,7-difluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(76)

(1S,3S)-5′-Chloro-6,7-difluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 8.06 (s, 1H), 7.40 (s, 1H), 7.33 (dd, J=8.5,2.0 Hz, 1H), 7.29-7.27 (m, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.99 (dd,J=10.0, 6.5 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.80-4.74 (m, 1H), 3.10(dd, J=15.5, 4.5 Hz, 1H), 2.97 (dd, J=15.5, 11.0 Hz, 1H), 2.14 (d, J=4.2Hz, 1H); MS (ESI) m/z 427.9 (M+H)⁺; [α]²⁵ _(D): −202.6°.

Example 93(1S,3S)-5′-Chloro-6-fluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(77)

(1S,3S)-5′-Chloro-6-fluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 7.71 (s, 1H), 7.26-7.20 (m,3H), 7.18 (d, J=2.0 Hz, 1H), 7.02-7.00 (m, 1H), 6.88 (d, JI=2.1 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 4.74-4.73 (m, 1H), 3.13-3.09 (m, 1H), 2.98 (dd,I=15.2, 11.0 Hz, 1H), 2.20 (d, J=6.6 Hz, 1H); MS (ESI) m/z 410.0 (M+H)⁺;[α]²⁵ _(D): −229.8°.

Example 94(1R,3R)-5′-Chloro-6-fluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(78)

(1R,3R)-5′-Chloro-6-fluoro-3-(trifluoromethyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 9.10 (s, 1H), 7.64 (s, 1H), 7.23 (dd, J=8.4,1.9 Hz, 1H), 7.19 (dd, J=9.2, 2.1 Hz, 2H), 7.03-7.01 (m, 1H), 6.88 (d,J=2.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 4.74-4.73 (m, 1H), 3.11 (dd,J=15.3, 4.3 Hz, 1H), 2.97 (dd, J=15.2, 11.0 Hz, 1H), 2.18 (d, J=7.2 Hz,1H); MS (ESI) m/z 410.0 (M+H)⁺; [α]²⁵ _(D): +220.8°.

Example 955′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one

(79)

5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.69 (s, 1H), 10.51 (s, 1H), 7.43 (m, 1H),7.32 (d, J=8.3 Hz, 1H), 7.26 (m, 1H), 7.04 (s, 1H), 6.93 (d, J=8.3 Hz,1H), 3.91 (m, 1H), 3.12 (bd, J=5.5 Hz, 1H), 2.77 (bd, J=14.2 Hz, 1H),2.38 (dd, J=14.2, 10.9 Hz, 1H), 1.16 (d, J=6.5 Hz, 1H); MS (ESI) m/z390.0 (M)⁺.

Example 965′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(80)

5′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, CDCl₃): δ 7.61 (bs, 1H), 7.34 (s, 1H), 7.30 (dd, J=9.0,3.0 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=3.0 Hz, 1H), 6.99 (m, 1H), 6.88(d, J=9.0 Hz, 1H), 4.21 (m, 1H), 2.91 (dd, J=15.0, 3.0 Hz, 1H), 2.51(dd, J=15.0, 9.0 Hz, 1H), 1.32 (d, J=6.0 Hz, 1H); MS (ESI) m/z 374.0(M+H)⁺.

Example 97(1R,3S)-5′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(81)

(1R,3S)-5′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.66 (bs, 1H), 10.49 (bs, 1H), 7.44 (m,1H), 7.33 (dd, J=8.5, 2.0 Hz, 1H), 7.11 (m, 1H), 7.04 (d, J=2.0 Hz, 1H),6.93 (d, J=8.5 Hz, 1H), 3.91 (m, 1H), 3.10 (bd, J=6.0 Hz, 1H), 2.76 (dd,J=15.0, 3.5 Hz, 1H), 2.38 (dd, J=15.5, 10.5 Hz, 1H), 1.17 (d, J=6.5 Hz,1H); MS (ESI) m/z 374.0 (M+H)⁺; [α]²⁵ _(D): +198.4°.

Example 98(1S,3R)-5′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(82)

(1S,3R)-5′-Chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (500 MHz, DMSO-d₆): δ 10.66 (bs, 1H), 10.49 (bs, 1H), 7.44 (m,1H), 7.33 (dd, J=8.0, 2.0 Hz, 1H), 7.11 (m, 1H), 7.04 (d, J=1.5 Hz, 1H),6.93 (d, J=8.5 Hz, 1H), 3.91 (m, 1H), 3.10 (bd, J=5.5 Hz, 1H), 2.76 (dd,J=15.0, 3.5 Hz, 1H), 2.38 (dd, J=15.0, 10.5 Hz, 1H), 1.19 (d, J=7.0 Hz,1H); MS (ESI) m/z 374.0 (M+H)⁺; [α]²⁵ _(D): −210.7°.

Example 995′-Chloro-6-fluoro-4-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one(83)

5′-Chloro-6-fluoro-4-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one:¹H NMR (300 MHz, DMSO-d₆): δ 10.61 (s, 1H), 10.59 (s, 1H), 7.32 (m, 2H),7.15 (dd, J=9.0, 3.0 Hz, 1H), 7.07 (d, J=3.0 Hz, 1H), 6.93 (d, J=9.0 Hz,1H), 6.87 (td, J=9.0, 3.0 Hz, 1H), 3.13 (m, 5H), 1.33 (d, J=6.0 Hz, 3H);MS (ESI) m/z 356.3 (M+H)⁺.

II. Antiparasitic Activity of Compounds of the Invention

The compounds of the invention are active against parasites causingmalaria, leishmaniasis and Chagas disease. The activities of thecompounds of the invention may be shown in standard in vitro and in vivotests.

Example A In Vitro Assay Representative Malaria Strain

The compounds of the invention and standard compounds are tested invitro against two standard parasite strains: Plasmodium falciparum, NF54(sensitive to all known drugs) and Plasmodium falciparum, K1(chloroquine and pyrimethamine resistant). Chloroquine diphosphate(Sigma C6628), artemisinin (Sigma 36159-3), artesunate (Mepha),atovaquone (GSK) and proguanil (Roche) are used as the standard drugs.The testing is carried out in 96-well plates (Costar™ 96-well microtiterplates).

Smears of the stock cultures of the two strains are prepared and theparasitemia for each culture is determined. Cultures with parasitemialower than 2% are not used.

Stock compound solutions are prepared in DMSO at 10 mg/mL. If insolublein DMSO, other solvents may be used according to the recommendations ofthe supplier. The stocks may be kept at 4° C. for typically 2 or moreweeks. For the assays, the compounds are further freshly diluted (4×dilution) with a screening medium (RPMI 1640 (10.44 g/L) (nohypoxanthine) supplemented with HEPES (5.94 g/L), NaHCO₃ (2.1 g/L),Neomycin (100 μg/mL)+Albumax^(R) II(5 g/L)).

100 μL of the screening medium is added to each well of the microtiterplate using a multipette.

An infected red cells solution comprising parasitemia (p) of 0.3% andhematocrit (h) of 2.5% is prepared. Accordingly, the finalconcentrations of p and h in the assay are 0.3 and 1.25%, respectively.

Mix 0.3 ml of infected culture with 0.47 mL of blood and 9.23 ml ofscreening medium to obtain 10 ml of a final solution at 0.3%parasitemia/2.5% hematocrit.

1 mL of uninfected red cells solution (no parasites, 2.5% hematocrit) isprepared by mixing 50 μL of washed human erythrocytes or red blood cells(50% hematocrit; any blood group) with 950 μL of the screening medium.

100 μL of the screening medium containing 4× the highest compoundconcentration is added to the wells in row B. Six drugs can be tested inthis manner on each plate. A reference substance is tested as well foreach assay.

Serial drug dilutions are prepared with a multichannel pipette. 100 μLis taken from the wells of row B and transferred, after gentle mixing,to the wells of row C. After mixing, 100 μL is transferred from thewells of row C to the wells of row D. This is repeated consecutively foreach row until row H. The 100 μL removed from the wells of row H arediscarded. A two-fold serial dilution of drugs is thus obtained. Forcompounds that are too active, the highest concentration isappropriately lowered. The wells of row A serve as controls withoutdrug.

100 μL of infected blood (parasitemia of 0.3%, 2.5% hematocrit) is addedto each well with a multipette with a yellow tip on top to avoidspillage. Only the control wells (i.e. wells A9-A12) receive uninfectedblood of 2.5% hematocrit.

The plates are incubated in an incubation chamber at 37° C. in anatmosphere containing a gas mixture of 93% N₂, 4% CO₂, and 3% O₂.

After 48 hours, 50 μL of ³H-hypoxanthine (=0.5 μCi) solution is added toeach well of the plate. The plates are incubated for another 24 hoursand may be frozen thereafter. If frozen, the plates are thawed for 1.5hours before harvesting. The ³H-hypoxanthine solution is prepared bydiluting a stock of 5 mCi/5 mL ex Amersham in half with 50% EtOH andthen diluting 1 mL aliquots to 1/50 with the screening medium.

The plates are harvested with a Betaplate™ cell harvester (Wallac,Zurich, Switzerland), which transfers the red blood cells onto a glassfiber filter and washes the filters with distilled water. The driedfilters are inserted into a plastic foil with 10 mL of scintillationfluid and counted in a Betaplate™ liquid scintillation counter (Wallac,Zurich, Switzerland). The results are recorded as counts per minute(cpm) per well at each drug concentration.

Data is transferred into a graphic programme (e.g. EXCEL) and expressedas percentage of the untreated controls. The 50% inhibitoryconcentration (IC₅₀) value is evaluated by Logit regression analysis.

Thus for the novel compounds Examples 50 and 62:

NF54 (CQ sensitive P. falciparum strain)IC₅₀=0.9 nM Example 50 IC₅₀=3.4nM Example 62

Example B In Vivo Assay

The compounds of the invention are tested in vivo against standardparasite strains:

a) Representative Malaria (Plasmodium) Strain

The Plasmodium berghei, GFP ANKA strain described in B. Franke-Fayard etal., Mol. Biochem. Parasitol., 137(1), 23-33, 2004 is used. This strainis maintained in female NMRI mice (20-22 g). The mice are kept inStandard Macrolon cages type II under standard conditions at 22° C. and60-70% relative humidity, on a diet of pellets (PAB45—NAFAG 9009,Provimi Kliba AG, CH-4303 Kaiseraugst, Switzerland) and water ad libitu.Chloroquine (Sigma C6628) and artemisinin (Sigma 36, 159-3) are used asthe standard drugs.

Stock compound solutions are prepared in 100% DMSO (suspended) or asolution consisting of 70% Tween-80 (d=1.08 g/mL) and 30% ethanol(d=0.81 g/mL), followed by a 10-fold dilution in H₂O.

On day 0, heparinized blood (containing 50 μL of 200 μg/mL Heparin) istaken from a donor mouse with approximately 30% parasitaemia and dilutedin physiological saline to 10⁸ parasitized erythrocytes per mL. Of thissuspension, 0.2 mL is injected intravenously (i.v.) into experimentalgroups of three mice, and a control group of five mice. Four hourspost-infection, the experimental groups are treated with a single doseby the intraperitoneal (i.p.) route. Other routes of application arepossible.

On days 1, 2 and 3 (24, 48 and 72 hours post-infection), theexperimental groups are treated with a single daily dose per oral dosing(p.o). Other routes of application are possible. The dosage isdetermined by a preliminary toxicity test. A typical dosage of 50mg/kg/day may be used for a compound of the invention. The drugconcentration is adjusted such that 0.1 mL/10 g is injected.

On day 4, 24 hours after the last drug treatment, 1 μL tail blood istaken and dissolved in 1 mL PBS buffer. Parasitaemia is determined witha FACScan (Becton Dickinson) by counting 100,000 red blood cells. Thedifference between the mean value of the control group and those of theexperimental groups is calculated and expressed as a percentage relativeto the control group (=activity). For parasitemias lower than 0.1%, thepresence of parasites in the FACS gate is checked visually (Fluorescence>10² is considered as positive). The survival of the animals ismonitored for up to 30 days. Mice surviving for 30 days are checked forparasitaemia and subsequently euthanised. A compound is consideredcurative if the animal survives to day 30 post-infection with nodetectable parasites.

The results obtained are expressed as 1) a reduction of parasitaemia onday 4 in % as compared to the untreated control group, and 2) meansurvival compared to the untreated control group.

Thus for the novel compounds (examples 50 and 62):

ED50 in P. berghei mouse model (mg/kg) 1.2 (example 50) 1.5 (example62)

INDUSTRIAL APPLICABILITY

The compounds of the invention have useful pharmaceutical properties. Inparticular, the compounds are useful in the treatment and prevention ofinfections such as those caused by parasites of

a) Plasmodium eg Plasmodium falciparum, Plasmodium vivax, Plasmodiummalariae, and Plasmodium ovale,b) Leishmania genus such as, for example, Leishmania donovani, andc) Trypanosoma eg Trypanosoma cruzi, and Chagas disease

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

1. A compound of formula (I), or a pharmaceutically acceptable salt,ester or prodrug thereof:

wherein m is 1 or 2; R1 is H, halogen, alkyl, haloalkyl, alkoxy, amineor aryl optionally substituted with one or more substituents; R2 is H,alkyl, arylalkyl or alkoxycarbonyl; R3 is H or alkyl; R4 is H, alkyl,hydroxyalkyl, —COOD wherein D is an alkyl group or R3 and R4 form partof a heterocyclo ring; R5 is H or alkyl; n is 1, 2 or 3; and A and B arefused to and form part of an unsubstituted or substituted monocyclic orpolycyclic arene or heteroarene; provided that if A and B are fused topositions 2 and 3 of an unsubstituted indole, n is 1 or 2, R2 and R3 areH, m is 1 and R1 is in position 6 of the spiro oxindole, then R1, R4 andR5 are not all H; or if R1 is H, then R4 is not methyl when R5 is H andR5 is not methyl when R4 is H; or if R1 is Br, then R4 and R5 are notboth H, and R4 is not methyl when R5 is H, and R5 is not methyl when R4is H.
 2. A compound of formula (II), or a pharmaceutically acceptablesalt, ester or prodrug thereof:

wherein: m is 1 or 2; R1 is H, halogen, alkyl, haloalkyl, alkoxy, amineor aryl optionally substituted with one or more substituents; R2 is H,alkyl, arylalkyl or alkoxycarbonyl; R3 is H or alkyl; R4 is H, alkyl,hydroxyalkyl, —COOD wherein D is an alkyl group or R3 and R4 form partof a heterocyclo ring; R5 is H or alkyl; n is 1, 2 or 3; and A and B arefused to and form part of an unsubstituted or substituted monocyclic orpolycyclic arene or heteroarene.
 3. The compound of claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof, wherein Aand B are fused to and form part of an unsubstituted or substitutedindole.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt, ester or prodrug thereof, wherein m is 1 and R1 is Cl and inposition 6 of the spiro oxindole.
 5. The compound of claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof, wherein n is1, R3 is H and one of R4 and R5 is methyl.
 6. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, in combination with apharmaceutically acceptable excipient, diluent or carrier.
 7. Thepharmaceutical composition of claim 6 further comprising a second drugsubstance.
 8. The compound of claim 2, or a pharmaceutically acceptablesalt, ester or prodrug thereof, wherein A and B are fused to and formpart of an unsubstituted or substituted indole.
 9. The compound of claim2, or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein m is 1 and R1 is Cl and in position 6 of the spiro oxindole. 10.The compound of claim 2, or a pharmaceutically acceptable salt, ester orprodrug thereof, wherein n is 1, R3 is H and one of R4 and R5 is methyl.11. A pharmaceutical composition comprising the compound of claim 2, ora pharmaceutically acceptable salt, ester or prodrug thereof, incombination with a pharmaceutically acceptable excipient, diluent orcarrier.
 12. The pharmaceutical composition of claim 11 furthercomprising a second drug substance.
 13. A method of treating orpreventing a parasitic infection, comprising administering to a patientin need thereof an effective amount of a compound of formula (III):

wherein m is 1 or 2; R1 is H, halogen, alkyl, haloalkyl, alkoxy, amineor aryl optionally substituted with one or more substituents; R2 is H,alkyl, arylalkyl or alkoxycarbonyl; R3 is H or alkyl; R4 is H, alkyl,hydroxyalkyl, —COOD wherein D is an alkyl group or R3 and R4 form partof a heterocyclo ring; R5 is H or alkyl; n is 1, 2 or 3; and A and B arefused to and form part of an unsubstituted or substituted monocyclic orpolycyclic arene or heteroarene, or a pharmaceutically acceptable salt,ester or prodrug thereof.
 14. A method of treating or preventing adisease caused by an infection by a parasite, comprising administeringto a patient in need thereof a compound of formula (III):

wherein m is 1 or 2; R1 is H, halogen, alkyl, haloalkyl, alkoxy, amineor aryl optionally substituted with one or more substituents; R2 is H,alkyl, arylalkyl or alkoxycarbonyl; R3 is H or alkyl; R4 is H, alkyl,hydroxyalkyl, —COOD wherein D is an alkyl group or R3 and R4 form partof a heterocyclo ring; R5 is H or alkyl; n is 1, 2 or 3; and A and B arefused to and form part of an unsubstituted or substituted monocyclic orpolycyclic arene or heteroarene, or a pharmaceutically acceptable salt,ester or prodrug thereof.
 15. A pharmaceutically acceptable salt, esteror prodrug of(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one.16.(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one.17.(1R,3S)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one.18. A pharmaceutically acceptable salt, ester or prodrug of,(1R,3S)-5′-Chloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol-2′(1′H)-one.